Benzofuran type derivatives, a composition comprising the same for treating or preventing cognitive dysfunction and the use thereof

ABSTRACT

The present invention relates to the novel benzofuran derivatives, the preparation thereof and the composition comprising the same. The benzofuran derivatives of the present invention showed potent inhibiting activity of beta-amyloid aggregation and cell cytotoxicity resulting in stimulating the proliferation of neuronal cells as well as recovering activity of memory learning injury caused by neuronal cell injury using transformed animal model with beta-amyloid precursor gene, therefore the compounds can be useful in treating or preventing cognitive function disorder.

TECHNICAL FIELD

The present invention relates to novel benzofuran type derivatives, acomposition comprising the same having preventing and treating activityof cognitive dysfunction disease and the use thereof.

BACKGROUND ART

CNS (Central Nervous System) consisting of brain and spinal cord whichplays a main role in regulating life phenomenon is a essential organgoverning all the human function through from sensory and (in)voluntarymovement to thinking, memory, motion, language etc. Accordingly, arapidly progressed apoptosis of neuronal cell caused by stroke, traumaetc as well as slowly progressed apoptosis such as degenerative diseaseoccurring in CNS caused by senile dementia for example, Alzheimer'sdisease or Parkinson disease etc result in irreversible functionaldisorder of neuronal network, which give rise to immortal failure ofhuman function in the end. Among them, the patients suffering fromAlzheimer disease, a representative senile dementia have been increasedin proportion to both of extended life-span and modernized welfarefacility. According to the public survey of Korea Institute for Healthand Social Affair, the ratio of older people among Korean people exceeds7% in 2000, reaches to 8.3% (3,970,000) and shall approach to 14.4% in2019. Especially, the ratio of more than 65 years old patient sufferingwith senile dementia is presumed to 8.2% in Korea. In Western countries,about 10% among more than 65 years old and about 40-50% among 80 yearsold patient suffers with senile dementia. Since more than five millionpatients suffer with the disease, the medical expense caused thereby ispresumed to hundred billion dollars in a year. There have been foundthat more than about two hundred thousand people are suffering fromdementia in Korea. In America, it has been presumed the number of thepatients be increased to two fold than the number of present patients in2030 and fourteen million (more than 350%) in 2050.

Since Alzheimer's disease initiated with cognitive function disorder isone of long-term degenerative diseases resulting in the breakdown ofhuman nature, there have been tried to develop effective and preventivedrugs till now, for example, acetylcholineesterase inhibitor such asAricept® (Pfizer Co.), Exelon (Novartis Co.), Reiminyl® (Janssen Co.) orNMDA receptor antagonist such as Ebixa (Lundbeck Co.). However, theacetylcholine esterase inhibitor could just alleviate reduced cognitiveability and could not satisfactorily treat etiological cause of thedisease. Although the drug shows temporarily alleviated effect on onlysome of patients (about 40-50%), it could not maintain it's potency fora long time moreover it shows various adverse response such ashepato-toxicity, vomiting, anorexia in case of long-term treatment.Accordingly, there has been urgently needed to develop new therapeuticagent to prevent and treat the disease nowadays. Many multi-nationalpharmaceutical companies have been invested on the development in alarge scale and in particular, focused in the development for beta- orgamma secretase inhibitor reducing the reproduced amount of beta-amyloidconsisting of about 40 amino acids which has been presumed to be anetiological factor of Alzheimer disease. The basic study on theAlzheimer disease has been actively attempted in Korea however thedevelopment of Alzheimer treating agent has been merely progressed tillnow. Since there have been found in animal model test as well asclinical trial that the development of gamma secretase inhibitor isassociated with considerable toxicity, it has been proved to be notrecommendable whereas the development of beta secretase inhibitor isrecommendable as proven by gene deficiency transformed animal modeltest. It is also regarded as a safe tool to focus on targeting thefactors involved in beta amyloid aggregation. There has been reportedthat ‘phenserine’ developed by Axonyx Co. in USA has been progressed inClinical trial 2 phase and it shows dual activities of inhibitingcholinesterase as well as beta amyloid aggregation. (Greig et al., J.Med. Chem., 44, pp. 4062-4071, 2001; www.medicalnewstoday.com;www.alzforum.org/drg/drc)

The development of vaccine using beta amyloid has been known as anotherpossible method. There has been reported that the serial study on thevaccine progressed by Elan Co. failed because of its un-predictableadverse response such as encephalitis during clinical trial. However, ithas been reported that beta amyloid vaccine could alleviate cognitivefunction in animal model test and improve the activity of brain cell aswell as damaged brain neuronal cells, resulting in alleviating Alzheimersyndrome. (Janus et al., Nature, 408, pp. 979-982, 2000; Morgan et al.,Nature, 408, pp. 982-985, 2000)

To investigate novel benzofuran derivatives having potent inhibitingeffect on cognitive function disorder through already well-knownscreening tests, the inventors of the present invention have intensivelyscreened various benzofuran derivatives showing potent inhibitingactivity of beta-amyloid aggregation and memory learning recovery studyusing passive avoidance test etc, and finally completed presentinvention by confirming that the benzofuran derivatives inhibitsbeta-amyloid aggregation and cell cytotoxicity resulting in stimulatingthe proliferation of neuronal cells as well as recovers memory learninginjury caused by neuronal cell injury.

These and other objects of the present invention will become apparentfrom the detailed disclosure of the present invention providedhereinafter.

DISCLOSURE Technical Problem

The present invention provides novel benzofuran derivatives and thepharmacologically acceptable salt thereof showing potent inhibitingeffect on cognitive function disorder.

The present invention also provides a pharmaceutical compositioncomprising novel benzofuran derivatives and the pharmacologicallyacceptable salt thereof as an active ingredient in an effective amountto treat and prevent cognitive function disorder.

The present invention also provides a use of novel benzofuranderivatives and the pharmacologically acceptable salt thereof for thepreparation of pharmaceutical composition to treat and prevent cognitivefunction disorder.

The present invention also provides a method of treating or preventingcognitive function disorder in a mammal comprising administering to saidmammal an effective amount of novel benzofuran derivatives and thepharmacologically acceptable salt thereof, together with apharmaceutically acceptable carrier thereof.

The present invention also provides a health functional food comprisingnovel benzofuran derivatives for the prevention or alleviation ofcognitive function disorder.

Technical Solution

The present invention provides a novel compound represented by thefollowing general formula (I), and the pharmaceutically acceptable saltthereof:

wherein

R₁ is at least one selected from the group consisting of a hydrogenatom, C₁-C₆ alkyl group, C₂-C₆ alkyl ketone group and —(CH₂)n-Q, ofwhich Q is an ether group or amine group substituted with C₁-C₆ loweralkyl group;

R₂ is a hydrogen atom, or an ether group or thio group substituted withC₁-C₆ alkyl group;

R₃ is a group selected from following substituents of general formula(Ia), (Ib), (Ic) or (Id),

wherein R′ is a hydrogen atom, or C₁-C₆ alkyl group,

X is at least one selected from amine group unsubstituted or substitutedwith O, S or R″, of which R″ is a benzyl group substituted with estergroup or carboxyl group,

n is an integer of 0-9;

-   -   wherein R′″ is at least one selected from a hydrogen atom, C₁-C₆        alkyl group or benzyl group,

n is an integer of 0-9;

wherein P₁, P₂ is independently, at least one selected from the groupconsisting of a hydrogen atom, C₁-C₆ alkyl group, phenyl group, benzylgroup and 2-methyl-3-acetamide group,

n is an integer of 0-9;

wherein X is C, O, S or N atom,

m is an integer of 0 or 1,

Q is a phenyl group substituted with C₁-C₃ alkyl group, halogen atom, ornitro group,

n is an integer of 0-9.

As preferable compounds of general formula (I), the compounds of thepresent invention wherein R₁ is a methyl group, ethyl group,methylketone group or ethyl ketone group; Q is a methoxy group, anethoxy group, dimethylamino group or diethylamino group; R₂ is ahydrogen atom or methylthio group; R₃ is selected from the group ofgeneral formula (Ia) wherein X is an oxygen atom or an ester groupsubstituted with benzyl group; a group of general formula (Ib) whereinR′″ is a methyl group, an ethyl group or a benzyl group; a group ofgeneral formula (Ic) wherein P₁, P₂ is independently a methyl group, anethyl group, a dimethyl group, diethyl group or 2-methyl-3-acetamidegroup; a group of general formula (Id) wherein Q is a phenyl groupsubstituted with a methyl group or an ethyl group are more preferable.

The most preferred compound of general formula (I) is one selected fromthe group consisting of;

Among the group of general formula (Ia),

-   3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-propanol,-   2-methoxy-4-[5-(3-methoxy-propyl)-3-methylsulfanyl-benzofuran-2-yl]-1-phenol,-   2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-ethanol,-   2-methoxy-4-[5-(2-methoxy-ethyl)-3-methylsulfanyl-benzofuran-2-yl]-phenol,-   3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-1-propanol,-   2-methoxy-4-[5-(3-methoxy-propyl)-benzofuran-2-yl]-phenol,-   2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-1-ethanol,-   3-[2-(3,4-dimethoxyphenyl)-3-methylsufanyl-benzofuran-5-yl]-propan-1-ol,-   2-(3,4-dimethoxyphenyl)-5-(3-methoxy-propyl)-3-methylsufanyl-benzofuran,-   2-[2-(3,4-dimethoxyphenyl)-3-methylsufanyl-benzofuran-5-yl]-ethanol,-   2-(3,4-dimethoxyphenyl)-5-(2-methoxy-ethyl)-3-methylsufanyl-benzofuran,-   3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propan-1-ol,-   2-(3,4-dimethoxy-phenyl)-5-(3-methoxy-propyl)-benzofuran,-   2-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-ethanol,-   2-(3,4-dimethoxy-phenyl)-5-(2-methoxy-ethyl)-benzofuran,-   3-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxy-phenyl}-3-(methylthio)-benzofuran-5-yl]-1-propanol,-   2-(3-methoxy-4-methoxymethoxy-phenyl)-5-(3-methoxy-propyl)-3-methylsulfanyl-benzofuran,-   5-(2-methoxy-ethyl)-2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran,-   3-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxy-phenyl}-3-benzofuran-5-yl]-1-propanol,-   3-[2-{4′-hydroxy-3′-methoxy-phenyl}-3-(methylthio)-benzofuran-5-yl]-propylamine,-   Benzyl    N-3-[2-{4′-hydroxy-3′-methoxyphenyl}-3-(methylthio)-benzofuran-5-yl]-propylcarbamate,-   2-[2-{4′-hydroxy-3′-methoxy-phenyl}-3-(methylthio)-benzofuran-5-yl]-ethylamine,-   Benzyl    N-2-[2-{4′-hydroxy-3′-methoxyphenyl}-3-(methylthio)-benzofuran-5-yl]-ethylcarbamate,-   2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanoic    acid,-   5-Allyloxy-2-(3,4-dimethoxy-phenyl)-benzofuran,-   2-(3,4-dimethoxyphenyl)-N-propylbenzofuran-5-amine,-   2-(3,4-Dimethoxy-phenyl)-5-propoxy-benzofuran;

Among the group of general formula (Ib),

-   Methyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionate,-   Benzyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionate,-   3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionic    acid,-   Methyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate,-   Benzyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate,-   2-[2-(4′ hydroxy-3′    methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetic acid,-   [2-(3,4-dimethoxyphenyl)-benzofuran-5-yl]acetic acid,-   3-[2-(4′ hydroxy-3-(methoxyphenyl)-benzofuran-5-yl]propionic acid,-   Methyl 2-[2-(4′ hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]acetate,-   2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]acetic acid,-   3-[2-(3,4-dimethoxyphenyl)-3-methylsufanyl-benzofuran-5-yl]-propionic    acid,-   3-[2-(3,4-dimethoxyphenyl)-3-methylsufanyl-benzofuran-5-yl]-propionic    acid methyl ester,-   [2-(3,4-dimethoxyphenyl)-3-methylsulfanyl-benzofuran-5-yl]acetic    acid,-   [2-(3,4-dimethoxyphenyl)-3-methylsulfanyl-benzofuran-5-yl]acetic    acid methyl ester,-   3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propionic acid,-   3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propionic acid methyl    ester,-   [2-(3,4-dimethoxyphenyl)-benzofuran-5-yl]acetic acid methyl ester,-   Methyl    3-[2-(4′-acetoxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionate,-   Methyl    2-[2-(4′-acetyloxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate,-   Methyl    3-[2-(4′-{4-[3-(diethylamino)propoxy]-3′-methoxy-phenyl}-3-(methylthio)-benzofuran-5-yl]-1-propionate,-   Methyl 2-[4-(acetyloxy)-3-methoxyphenyl]-1-benzofuran-5-yl-acetate,-   Methyl    3-[2-(4′-acetoxy-3′-methoxyphenyl)-benzofuran-5-yl]propionate,-   Methyl    3-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxy-phenyl}-benzofuran-5-yl]-1-propionate,-   Methyl    2-(2-(4-acetoxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanoate,-   Methyl 2-(2-(4-acetoxy-3-methoxyphenyl)benzofuran-5-yl)propanoate;

Among the group of general formula (Ic),

-   N,N-diethyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,-   N,N-dimethyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,-   N-methyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,-   N,N-diethyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,-   N,N-dimethyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,-   N-methyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,-   (R)-2-(2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide-4-methylpentanamide,-   N-phenyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,-   N-benzyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,-   (R)-3-(2-[2-(4-hydroxy-3-methoxyphenyl)-3-(methylsulfanyl)-1-benzofuran-5-yl]-acetylamino-4-methylpentanamide,-   N-phenyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,-   N-benzyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,-   2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide,-   3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionamide,-   3-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dipropylpropanamide,-   3-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dipropylpropanamide,-   2-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dimethylacetamide,-   N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanamide,-   2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N-propylacetamide,-   N,N-Diethyl-3-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)propanamide,-   N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)acetamide,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dipropylacetamide,-   N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)propanamide,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dimethylpropanamide,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dipropylpropanamide,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N-propylpropanamide,-   N,N-Diethyl-2-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)acetamide,-   2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-N,N-dimethylacetamide,-   N-[2-(3,4-Dimethoxy-phenyl)-benzofuran-5-yl]-propionamide,-   N-[2-(3,4-Dimethoxy-phenyl)-benzofuran-5-yl]-butyramide,-   Butyl-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-amine;

Among the group of general formula (Id),

-   Methyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-propionate,-   2-[2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-1-ethanol,-   3-[2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propan-1-ol,-   2-methoxy-4-[5-(2-methoxy-ethyl)-benzofuran-2-yl]-phenol,-   Pentafluorophenyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate,-   Pentafluorophenyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionate,-   Pentafluorophenyl    2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-acetate,-   Pentafluorophenyl    3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-propionate,-   2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-morpholino-1-ethanone,-   2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-piperazino-1-ethanone,-   2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperazino)-1-ethanone,-   2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperidino)-1-ethanone,-   3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-morpholino-1-propanone,-   3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-piperazino-1-propanone,-   3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperazino)-1-propanone,-   3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperidino)-1-propanone,-   Methyl    3-{2-[4′-(3-chloropropoxy)-3′-methoxyphenyl]-3-(methylthio)-benzofuran-5-yl]propionate,-   [2-(3,4-dimethoxyphenyl)-3-methylsulfanyl-benzofuran-5-yl]acetic    acid pentafluorophenyl ester,-   3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]propionic    acid pentafluorophenyl ester,-   [2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]acetic acid    pentafluorophenyl ester,-   3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]propionic acid    pentafluorophenyl ester,-   2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-1-(4-phenyl-piperazin-1-yl)-ethanone,-   3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-1-(4-phenyl-piperazin-1-yl)-propan-1-one,-   1-(4-benzyl-piperazin-1-yl)-2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanone,-   1-(4-benzyl-piperazin-1-yl)-3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propan-1-one,-   2-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-1-(4-phenyl-piperazine-1-yl)    ethanone,-   3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-1-(4-phenyl-piperazine-1-yl)    propan-1-one,-   1-(4-benzyl-piperazin-1-yl)-2-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-ethanone,-   1-(4-benzyl-piperazin-1-yl)-3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propan-1-one,-   3-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one,-   3-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-one,-   3-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one,-   3-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-one,-   2-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)ethanone,-   2-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanone,-   2-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(4-methylpiperazin-1-yl)ethanone,-   2-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one,-   2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)ethanone,-   2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)ethanone,-   2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-morpholinoethanone,-   2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)ethanone,-   2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanone,-   3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-one,-   3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one,-   3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-morpholinopropan-1-one,-   3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)propan-1-one,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)ethanone,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(pyrrolidi    n-1-yl)ethanone,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanone,-   1-(4-Benzylpiperidin-1-yl)-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)ethanone,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(4-phenylpiperazin-1-yl)ethanone,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)propan-1-one,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-morpholinopropan-1-one,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)propan-1-one,-   2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-one,-   2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)ethanone,-   2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)ethanone,-   2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-morpholinoethanone,-   2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)ethanone,-   1-(4-Benzylpiperidin-1-yl)-2-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)ethanone,-   2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperazin-1-yl)ethanone,-   3-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one.

The inventive compounds represented by general formula (I) can betransformed into their pharmaceutically acceptable salt and solvates bythe conventional method well known in the art. For the salts,acid-addition salt thereof formed by a pharmaceutically acceptable freeacid thereof is useful and can be prepared by the conventional method.For example, after dissolving the compound in the excess amount of acidsolution, the salts are precipitated by the water-miscible organicsolvent such as methanol, ethanol, acetone or acetonitrile to prepareacid addition salt thereof and further the mixture of equivalent amountof compound and diluted acid with water or alcohol such as glycolmonomethylether, can be heated and subsequently dried by evaporation orfiltrated under reduced pressure to obtain dried salt form thereof.

As a free acid of above-described method, organic acid or inorganic acidcan be used. For example, organic acid such as methansulfonic acid,p-toluensulfonic acid, acetic acid, trifluoroacetic acid, citric acid,maleic acid, succinic acid, oxalic acid, benzoic acid, lactic acid,glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaricacid, glucuronic acid, aspartic acid, ascorbic acid, carbonylic acid,vanillic acid, hydroiodic acid and the like, and inorganic acid such ashydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaricacid and the like can be used herein.

Further, the pharmaceutically acceptable metal salt form of inventivecompounds may be prepared by using base. The alkali metal oralkali-earth metal salt thereof can be prepared by the conventionalmethod, for example, after dissolving the compound in the excess amountof alkali metal hydroxide or alkali-earth metal hydroxide solution, theinsoluble salts are filtered and remaining filtrate is subjected toevaporation and drying to obtain the metal salt thereof. As a metal saltof the present invention, sodium, potassium or calcium salt arepharmaceutically suitable and the corresponding silver salt can beprepared by reacting alkali metal salt or alkali-earth metal salt withsuitable silver salt such as silver nitrate.

The pharmaceutically acceptable salt of the compound represented bygeneral formula (I) comprise all the acidic or basic salt which may bepresent at the compounds, if it does not indicated specifically herein.For example, the pharmaceutically acceptable salt of the presentinvention comprise the salt of hydroxyl group such as the sodium,calcium and potassium salt thereof; the salt of amino group such as thehydrogen bromide salt, sulfuric acid salt, hydrogen sulfuric acid salt,phosphate salt, hydrogen phosphate salt, dihydrophosphate salt, acetatesalt, succinate salt, citrate salt, tartarate salt, lactate salt,mandelate salt, methanesulfonate(mesylate) salt and p-toluenesulfonate(tosylate) salt etc, which can be prepared by the conventional methodwell known in the art.

There may exist in the form of optically different diastereomers sincethe compounds represented by general formula (I) have unsymmetricalcenters, accordingly, the compounds of the present invention compriseall the optically active isomers, R or S stereoisomers and the mixturesthereof. Present invention also comprises all the uses of racemicmixture, more than one optically active isomer or the mixtures thereofas well as all the preparation or isolation method of the diastereomerwell known in the art.

The compounds of the invention of formula (I) may be chemicallysynthesized by the methods which will be explained by following reactionschemes hereinafter, which are merely exemplary and in no way limit theinvention. The reaction schemes show the steps for preparing therepresentative compounds of the present invention, and the othercompounds also may be produced by following the steps with appropriatemodifications of reagents and starting materials, which are envisaged bythose skilled in the art.

General Synthetic Procedures

As depicted in the above Scheme 1, the scheme explains the process forpreparing novel benzofuran derivatives (5-6) from conventionallyavailable or easily prepared starting materials well-known in the art asfollows:

At the 1^(st) step, 3-methoxy-4-hydroxy-benzaldehyde is acetylated withthe solvent to obtain acetylated intermediate compound (1). The solventwhich does not cause to adverse effect such as acetic acid, pyridine,THF etc may be used in the reaction. It is preferable that the reactiontemperature in the reaction can be performed at cool temperature to roomtemperature, preferably, at room temperature however it is not limitedthereto. It is preferable that the reaction period in the reaction canbe performed in the range from 5 hrs to 24 hrs, more preferably, 24 hrswith stirring to synthesize the intermediate (1).

At the 2^(nd) step, the brominated intermediate compound (2) can beprepared by reacting the intermediate (1) with the appropriate reagentsuch as bromine, 45% hydrogen bromide and acetate.

At the 3^(rd) step, the intermediate compound (3) can be prepared byreacting the intermediate (2) with the appropriate reagent such asNaSCH₃, Aliquat 336 and benzene/H₂O.

At the 4^(th) step, the intermediate compound (4) can be prepared byreacting the intermediate (3) with the appropriate reagent such asN-chloro-succiimide and CCl₄.

At the 5^(th) step, the intermediate compound (5) can be prepared byreacting the intermediate (4) with the appropriate reagent such as zincchloride, dichloromethane, 4-hydroxyphenylacetic acid (n=0) and3-(4-hydroxyphenyl)propionic acid methylester (n=1).

At the 6^(th) step, the intermediate compound (6) can be prepared byreacting the intermediate (5) with the appropriate reducing conditionsuch as Raney nickel and ethanol etc.

The solvent which does not cause to adverse effect, for example,dichloromethane, alcohol solvent such as methanol, ethanol etc, oracetone etc, preferably, ethanol may be used in the reaction.

As depicted in the above Scheme 2, the scheme explains the process forpreparing novel benzofuran derivatives (11-12) from conventionallyavailable or easily prepared starting materials well-known in the art asfollows:

At the 1^(st) step, the compounds (5-6) prepared in the above-describedstep is reacted to obtain the intermediate compound (7-8) underappropriate condition such as lithium hydroxide, water and THF etc.

At the 2^(nd) step, the compounds (7-8) prepared in the above-describedstep is reacted to obtain the intermediate compound (9-10) underappropriate condition such as potassium carbonate, water and ethanoletc.

The solvent which does not cause to adverse effect, for example,dimethylformamide, alcohol solvent such as methanol, ethanol etc oracetone may be used in the reaction. It is preferable that the reactiontemperature in the reaction can be performed at cool temperature to roomtemperature, preferably, at room temperature however it is not limitedthereto.

At the 3^(rd) step, the intermediate compound (11-12) can be prepared byreacting the intermediate (9-10) with the appropriate reagent such asLAH (lithium hydrogenated aluminum), THF etc.

As depicted in the above Scheme 3, the scheme explains the process forpreparing novel benzofuran derivatives (15-16) from conventionallyavailable or easily prepared starting materials well-known in the art asfollows:

At the 1^(st) step, the starting compound (11) prepared in theabove-described step is reacted to obtain the compound (13) underappropriate condition such as MOM-Cl, potassium carbonate and acetoneetc.

At the 2^(nd) step, the compounds (13) prepared in the above-describedstep is reacted to obtain the compound (14) under appropriate conditionsuch as sodium hydroxide, methyl iodide and TI-IF etc.

At the 3^(rd) step, the compounds (14) prepared in the above-describedstep is reacted to obtain the compound (15) under appropriate conditionsuch as trifluoroacetic acid and dichloromethane etc.

At the 4^(th) step, the compound (16) can be prepared by reacting theintermediate (15) with the appropriate reducing reagent such as Raneynickel and ethanol etc.

The solvent which does not cause to adverse effect, for example,dichloromethane, chloroform, dimethyl ether, THF, or alcohol solventsuch as methanol, ethanol etc may be used in the reaction. It ispreferable that the reaction temperature in the reaction can beperformed at cool temperature to room temperature, preferably, at roomtemperature however it is not limited thereto.

As depicted in the above Scheme 4, the scheme explains the process forpreparing novel benzofuran derivatives (17-18) from conventionallyavailable or easily prepared starting materials well-known in the art asfollows:

The starting compounds (11-12) prepared in the above-described step isreacted to obtain the compounds (17-18) under appropriate condition suchas sodium hydride, methyl iodide, and THF etc.

The solvent which does not cause to adverse effect, for example,dichloromethane, chloroform, dimethyl ether, THF, or alcohol solventsuch as methanol, ethanol etc may be used in the reaction. It ispreferable that the reaction temperature in the reaction can beperformed at cool temperature to room temperature, preferably, at roomtemperature however it is not limited thereto.

As depicted in the above Scheme 5, the scheme explains the process forpreparing novel benzofuran derivatives (22) from conventionallyavailable or easily prepared starting materials well-known in the art asfollows:

At the 1^(st) step, the starting compound (7) prepared in theabove-described Scheme 2 is reacted to obtain the compound (19) underappropriate condition such as benzyl alcohol, dimethylaminopyridine, andEDC etc.

At the 2^(nd) step, the compounds (19) prepared in the above-describedstep is reacted to obtain the compounds (20-21) under appropriatecondition such as pentafluorophenol, EDC, and dichloromethane dissolvedin DMF (Dimethylformamide) etc.

At the 3^(rd) step, the compounds (20-21) prepared in theabove-described step is reacted with amines having various substituentsto obtain the compound (22) under appropriate condition.

The solvent which does not cause to adverse effect, for example,dichloromethane, chloroform, dimethyl ether, THF, or alcohol solventsuch as methanol, ethanol etc may be used in the reaction. It ispreferable that the reaction temperature in the reaction can beperformed at cool temperature to room temperature, preferably, at roomtemperature however it is not limited thereto.

As depicted in the above Scheme 6, the scheme explains the process forpreparing benzofuran derivatives (25) from conventionally available oreasily prepared starting materials well-known in the art as follows:

At the 1^(st) step, the starting compound (20) prepared in theabove-described Scheme 5 is reacted to obtain the compound (23) underappropriate condition such as ammonia and methanol etc.

At the 2^(nd) step, the compound (23) prepared in the above-describedstep is reacted to obtain the compound (24) under appropriate conditionsuch as LAH and THF etc.

At the 3^(rd) step, the compound (24) prepared in the above-describedstep is reacted to obtain the compound (25) under appropriate conditionsuch as benzylchloroformate, TEA and THF etc.

The solvent which does not cause to adverse effect, for example,dichloromethane, chloroform, dimethyl ether, THF, or alcohol solventsuch as methanol, ethanol etc may be used in the reaction. It ispreferable that the reaction temperature in the reaction can beperformed at cool temperature to room temperature, preferably, at roomtemperature however it is not limited thereto.

As depicted in the above Scheme 7, the scheme explains the process forpreparing benzofuran derivatives (29-30) from conventionally availableor easily prepared starting materials well-known in the art as follows:

At the 1^(st) step, the starting compound (9) prepared in theabove-described Scheme 2 is reacted to obtain the compound (26) underappropriate condition such as 1-bromo-3-chloropropane, calciumcarbonate, and methanol etc.

At the 2^(nd) step, the compound (26) prepared in the above-describedstep is reacted to obtain the compound (27) under appropriate conditionsuch as diethylamine, and methanol etc.

At the 3^(rd) step, the compound (27) prepared in the above-describedstep is reacted to obtain the compound (28) under appropriate reducingcondition such as Raney nickel, and methanol etc.

At the 4^(th) step, the compound (28) prepared in the above-describedstep is reacted to obtain the compounds (29-30) under appropriatecondition such as LAH, and THF etc.

The solvent which does not cause to adverse effect, for example,dichloromethane, chloroform, dimethyl ether, THF, or alcohol solventsuch as methanol, ethanol etc may be used in the reaction. It ispreferable that the reaction temperature in the reaction can beperformed at cool temperature to room temperature, preferably, at roomtemperature however it is not limited thereto.

As depicted in the above Scheme 8, the scheme explains the process forpreparing benzofuran derivatives (37-38) from conventionally availableor easily prepared starting materials well-known in the art as follows:

At the 1^(st) step, the starting compounds (7-8) prepared in theabove-described Scheme 2 is reacted to obtain the compounds (31-32)under appropriate condition such as potassium carbonate, methyl iodide,and acetone etc.

At the 2^(nd) step, the compounds (31-32) prepared in theabove-described step is reacted to obtain the compounds (33-34) underappropriate condition such as lithium hydroxide dissolved in water andTHF in water etc.

At the 3^(rd) step, the compounds (33-34) prepared in theabove-described step is reacted to obtain the compounds (35-36) underappropriate condition such as pentafluorophenol, EDC and dichloromethaneetc.

At the 4^(th) step, the compounds (35-36) prepared in theabove-described step is reacted to obtain the compounds (37-38) underappropriate condition such as 1-phenylpiperazine, 1-benzylpiperazine,TEA and dichloromethane etc.

The solvent which does not cause to adverse effect, for example,dichloromethane, chloroform, dimethyl ether, THF, or alcohol solventsuch as methanol, ethanol etc may be used in the reaction. It ispreferable that the reaction temperature in the reaction can beperformed at cool temperature to room temperature, preferably, at roomtemperature however it is not limited thereto.

As depicted in the above Scheme 9, the scheme explains the process forpreparing benzofuran derivatives (39-40) from conventionally availableor easily prepared starting materials well-known in the art as follows:

The starting compounds (31-32) prepared in the above-described Scheme 8is reacted to obtain the compounds (39-40) under appropriate conditionsuch as LAH, and THF etc.

The solvent which does not cause to adverse effect, for example,dichloromethane, chloroform, dimethyl ether, THF, or alcohol solventsuch as methanol, ethanol etc may be used in the reaction. It ispreferable that the reaction temperature in the reaction can beperformed at cool temperature to room temperature, preferably, at roomtemperature however it is not limited thereto.

The novel benzofuran derivatives prepared by the above-described methodrepresented by general formula (I) shows potent inhibiting activity ofbeta-amyloid aggregation and cell cytotoxicity resulting in stimulatingthe proliferation of neuronal cells as well as recovering activity ofmemory learning injury caused by neuronal cell injury using transformedanimal model with beta-amyloid precursor gene, therefore the compoundscan be useful in treating or preventing cognitive function disorder.

Accordingly, it is another object of the present invention to providethe pharmaceutical composition comprising an efficient amount of thecompound represented by general formula (I) or the pharmaceuticallyacceptable salt thereof as an active ingredient in amount effective totreat or prevent cognitive function disorder, together withpharmaceutically acceptable carriers or diluents.

It is another object of the present invention to provide thepharmaceutical composition comprising an efficient amount of thecompound represented by general formula (I) or the pharmaceuticallyacceptable salt thereof as an active ingredient in amount effective totreat or prevent cognitive function disorder, together withpharmaceutically acceptable carriers or diluents.

In accordance with the other aspect of the present invention, there isalso provided a use of the compound represented by general formula (I)or the pharmaceutically acceptable salt thereof for manufacture ofmedicines employed for treating or preventing cognitive functiondisorder in mammals including human as an active ingredient in amounteffective to treat or prevent cognitive function disorder.

In accordance with the other aspect of the present invention, there isalso provided a use of the compound represented by general formula (I)or the pharmaceutically acceptable salt thereof for manufacture ofmedicines employed for treating or preventing cognitive functiondisorder in mammals including human as an active ingredient in amounteffective to treat or prevent cognitive function disorder.

In accordance with the other aspect of the present invention, there isalso provided a method of treating or preventing cognitive functiondisorder in a mammal comprising administering to said mammal aneffective amount of novel derivatives represented by general formula (I)and the pharmacologically acceptable salt thereof, together with apharmaceutically acceptable carrier thereof into the mammals includinghuman suffering from said disease.

In accordance with the other aspect of the present invention, there isalso provided a method of inhibiting accumulated beta-amyloid in amammal comprising administering to said mammal an effective amount ofnovel derivatives represented by general formula (I) and thepharmacologically acceptable salt thereof, together with apharmaceutically acceptable carrier thereof into the mammals includinghuman suffering from said disease.

The term “cognitive function disorder” disclosed herein comprise variouscognitive function disorder caused by accumulated beta-amyloid, forexample, Alzheimer type dementia, cerebrovascular type dementia, Pick'sdisease, Creutzfeldt-jakob's disease, dementia caused by cephalicdamage, Parkinson's disease, and the like, preferably, Parkinson'sdisease.

The compound according to the present invention can be provided as apharmaceutical composition containing pharmaceutically acceptablecarriers, adjuvants or diluents. For example, the compound of thepresent invention can be dissolved in oils, propylene glycol or othersolvents which are commonly used to produce an injection. Suitableexamples of the carriers include physiological saline, polyethyleneglycol, ethanol, vegetable oils, isopropyl myristate, etc., but are notlimited to them.

Hereinafter, the following formulation methods and excipients are merelyexemplary and in no way limit the invention.

The compound of the present invention in pharmaceutical dosage forms maybe used in the form of their pharmaceutically acceptable salts, and alsomay be used alone or in appropriate association, as well as incombination with other pharmaceutically active compounds.

The compound of the present invention may be formulated intopreparations for injections by dissolving, suspending, or emulsifyingthem in aqueous solvents such as normal saline, 5% Dextrose, ornon-aqueous solvent such as vegetable oil, synthetic aliphatic acidglycerides, esters of higher aliphatic acids or propylene glycol. Theformulation may include conventional additives such as solubilizers,isotonic agents, suspending agents, emulsifying agents, stabilizers andpreservatives.

The desirable dose of the inventive compound varies depending on thecondition and the weight of the subject, severity, drug form, route andperiod of administration, and may be chosen by those skilled in the art.However, in order to obtain desirable effects, it is generallyrecommended to administer at the amount ranging 0.0001-100 mg/kg,preferably 0.001-10 mg/kg by weight/day of the inventive compound of thepresent invention. The dose may be administered in single or dividedinto several times per day. In terms of composition, the compound shouldbe present between 0.0001 to 10% by weight, preferably 0.0001 to 1% byweight based on the total weight of the composition.

The pharmaceutical composition of present invention can be administeredto a subject animal such as mammals (rat, mouse, domestic animals orhuman) via various routes. All modes of administration are contemplated,for example, administration can be made by inhaled, orally, rectally orby intravenous, intramuscular, subcutaneous, intrathecal, epidural orintracerebroventricular injection.

The novel benzofuran derivatives represented by general formula (I) ofthe present invention also can be used as a main component or additiveand aiding agent in the preparation of various functional health foodand health care food.

Accordingly, it is the other object of the present invention to providea functional health food comprising novel benzofuran derivativesrepresented by general formula (I), or the pharmacologically acceptablesalt thereof for alleviating or improve cognitive function disorder inhuman or mammal.

The term “a functional health food” defined herein the functional foodhaving enhanced functionality such as physical functionality orphysiological functionality by adding the compound of the presentinvention to conventional food to prevent or improve cognitive functiondisorder in human or mammal.

It is the other object of the present invention to provide a health carefood comprising benzofuran derivatives represented by the followinggeneral formula (I), or the pharmacologically acceptable salt thereof,together with a sitologically acceptable additive for the prevention andalleviation of cognitive function disorder.

The term “a health care food” defined herein the food containing thecompound of the present invention showing no specific intended effectbut general intended effect in a small amount of quantity as a form ofadditive or in a whole amount of quantity as a form of capsule, pill,tablet etc.

The term “a sitologically acceptable additive” defined herein anysubstance the intended use which results or may reasonably be expectedto result—directly or indirectly—in its becoming a component orotherwise affecting the characteristics of any food for example,thickening agent, maturing agent, bleaching agent, sequesterants,humectant, anti-caking agent, clarifying agents, curing agent,emulsifier, stabilizer, thickner, bases and acid, foaming agents,nutrients, coloring agent, flavoring agent, sweetner, preservativeagent, antioxidant, etc, which shall be explained in detail as follows.

If a substance is added to a food for a specific purpose in that food,it is referred to as a direct additive and indirect food additives arethose that become part of the food in trace amounts due to itspackaging, storage or other handling.

Above described health foods can be contained in food, health beverage,dietary therapy etc, and may be used as a form of powder, granule,tablet, chewing tablet, capsule, beverage etc for preventing orimproving cognitive function disorder.

Also, above described compounds can be added to food or beverage forprevention and improvement of cognitive function disorder. The amount ofabove described compound in food or beverage as a functional health foodor health care food may generally range from about 0.01 to 100 w/w % oftotal weight of food for functional health food composition. Inparticular, although the preferable amount of the compound of thepresent invention in the functional health food, health care food orspecial nutrient food may be varied in accordance to the intendedpurpose of each food, it is preferably used in general to use as aadditive in the amount of the compound of the present invention rangingfrom about 0.01 to 5% in food such as noodles and the like, from 40 to100% in health care food on the ratio of 100% of the food composition.

Providing that the health beverage composition of present inventioncontains above described compound as an essential component in theindicated ratio, there is no particular limitation on the other liquidcomponent, wherein the other component can be various deodorant ornatural carbohydrate etc such as conventional beverage. Examples ofaforementioned natural carbohydrate are monosaccharide such as glucose,fructose etc; disaccharide such as maltose, sucrose etc; conventionalsugar such as dextrin, cyclodextrin; and sugar alcohol such as xylitol,and erythritol etc. As the other deodorant than aforementioned ones,natural deodorant such as taumatin, stevia extract such as levaudiosideA, glycyrrhizin et al., and synthetic deodorant such as saccharin,aspartam et al., may be useful favorably. The amount of above describednatural carbohydrate is generally ranges from about 1 to 20 g,preferably 5 to 12 g in the ratio of 100 of present beveragecomposition.

The other components than aforementioned composition are variousnutrients, a vitamin, a mineral or an electrolyte, synthetic flavoringagent, a coloring agent and improving agent in case of cheese, chocolateet al., pectic acid and the salt thereof, alginic acid and the saltthereof, organic acid, protective colloidal adhesive, pH controllingagent, stabilizer, a preservative, glycerin, alcohol, carbonizing agentused in carbonate beverage et al. The other component thanaforementioned ones may be fruit juice for preparing natural fruitjuice, fruit juice beverage and vegetable beverage, wherein thecomponent can be used independently or in combination. The ratio of thecomponents is not so important but is generally range from about 0 to 20w/w % per 100 w/w % present composition. Examples of addable foodcomprising aforementioned extract therein are various food, beverage,gum, vitamin complex, health improving food and the like.

The present invention is more specifically explained by the followingexamples. However, it should be understood that the present invention isnot limited to these examples in any manner.

Advantageous Effects

As described in the present invention, the novel benzofuran derivativesof the present invention showed potent inhibiting activity ofbeta-amyloid aggregation and cell cytotoxicity resulting in stimulatingthe proliferation of neuronal cells as well as recovering activity ofmemory learning injury caused by neuronal cell injury using transformedanimal model with beta-amyloid precursor gene, therefore the compoundscan be useful in treating or preventing cognitive function disorder.

DESCRIPTION OF DRAWINGS

The above and other objects, features and other advantages of thepresent invention will more clearly understood from the followingdetailed description taken in conjunction with the accompanyingdrawings, in which;

FIG. 1 shows the inhibition effect of inventive compounds on theaggregation of beta-amyloid and the lysis of aggregated beta-amyloid,

FIG. 2 shows the result of Y maze test using animal model treated withbeta-amyloid and inventive compounds,

FIG. 3 shows the result of Y maze test using animal model treated withvarious concentrations of inventive compound (18b) in a dose dependentmanner,

FIG. 4 represents the result of passive avoidance test using animalmodel treated with beta-amyloid and inventive compounds,

FIG. 5 represents the result of passive avoidance test using animalmodel treated with various concentrations of inventive compound (18b) ina dose dependent manner,

FIG. 6 represents the result of water maze test to determine the memorylearning capacity in the mice where beta-amyloid was injected into aventricle of their brains,

FIG. 7 presents the result of water maze test to determine the memorylearning capacity in the mice treated with beta-amyloid and inventivecompounds,

FIG. 8 depicts the result of cognitive capacity test memory to determinethe recovering activity of learning study using animal model treatedwith beta-amyloid and inventive compounds,

FIG. 9 depicts a neuron staining result of animal model having injuredlearning capacity caused by beta-amyloid treatment,

FIG. 10 depicts GFAP staining result of animal model having injuredlearning capacity caused by beta-amyloid treatment,

FIG. 11 depicts chAT staining result of animal model having injuredlearning capacity caused by beta-amyloid treatment,

FIG. 12 presents the determined result of Y maze test of ExperimentalExample 3-2-1,

FIG. 13 presents the determined result of Aβ-40 ELISA test ofExperimental Example 3-2-2,

FIG. 14 presents transformed percentage (%) of area of beta-amyloidaggregation in transgenic mice treated with inventive compound,

FIG. 15 presents the number of cholinergic neuron in transgenic micetreated with inventive compound.

BEST MODE

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compositions, use andpreparations of the present invention without departing from the spiritor scope of the invention.

The present invention is more specifically explained by the followingexamples.

However, it should be understood that the present invention is notlimited to these examples in any manner.

Mode for Invention

The following Reference Example, Examples and Experimental Examples areintended to further illustrate the present invention without limitingits scope.

Reference Example 1 Preparation of Intermediate (1):4-acetyl-2-methoxyphenyl acetate (1)

As shown in the above-described reaction formula, acetovanillone (500mg, 3 mM) dissolved in 20 ml of THF was mixed with 0.5 ml of pyridineand 0.6 ml of anhydrous acetic acid. The mixture was stirred for 3 hoursat room temperature. The resulting product was recovered with theextraction with diethylether and dried with anhydrous magnesium sulfateto remove remaining solvent. The remaining residue was performed toSilica gel column chromatography with a mobile phase(n-hexane:ethylacetate=4:1) to obtain white solid type of4-acetyl-2-methoxyphenyl acetate (1; 625 mg).

m.p: 58.7° C.;

¹H NMR (CDCl₃): δ ppm 7.60 (d, 1H, J=1.8 Hz, H-3), 7.55 (dd, 1H, J=1.8,8.2 Hz, H-5), 7.12 (d, 1H, J=8.2 Hz, H-6), 3.89 (s, 3H, OCH₃), 2.59 (s,3H, OCOCH₃), 2.33 (s, 3H, COCH₃).

Reference Example 2 Preparation of Intermediate (2):4-(2-bromoacetyl)-2-methoxyphenyl acetate (2)

As shown in the above-described reaction formula, the solutioncontaining 3.44 g of 4-acetyl-2-methoxyphenyl acetate (16.5 mM) wasadded to 7 ml of acetic acid dropwisely. 3 drops of 45% hydrobromic acidwas added thereto and then 0.85 ml of brome (16.5 mM) was slowly addedthereto.

The mixture solution was stirred to the extent that the product changedto colorless and the reaction mixture was cooled by adding 7 ml ofwater. The resulting product was extracted with dichloromethane, driedwith anhydrous magnesium sulfate and the remaining solvent was removed.The remaining residue was performed to Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of 4-(2-bromoacetyl)-2-methoxyphenyl acetate (2; 4.73 g).

Yield: 94%;

m.p: 82.0° C.;

¹H NMR (CDCl₃): δ ppm 7.63 (d, 1H, J=2 Hz, H-3), 7.58 (dd, 1H, J=2, 8Hz, H-5), 7.16 (d, 1H, J=8 Hz, H-6), 4.43 (s, 2H, CH₂Br), 3.91 (s, 3H,OCH₃), 2.34 (s, 3H, COCH₃).

Reference Example 3 Preparation of Intermediate(3):2-methoxy-4-[-2-(methylthio)acetyl]phenyl acetate (3)

As shown in the above-described reaction formula, the mixture of 600 mlof sodium methyl mercaptan (8.56 ml) and three drops of aliquat/5 ml ofwater solution was added to the solution containing 2.46 g of4-(2-bromoacetyl)-2-methoxyphenyl acetate (8.56 mM) dissolved in 10 mlof benzene. The mixture solution was stirred for 20 hours. The resultingproduct was extracted with ethylacetate, dried with anhydrous magnesiumsulfate and the remaining solvent was removed. The remaining residue wasperformed to Silica gel column chromatography with a mobile phase(n-hexane:ethylacetate=4:1) to obtain white solid type of2-methoxy-4-[-2-(methylthio)acetyl]phenyl acetate (3; 2.18 g).

Yield: 83%;

m.p=70.4° C.;

1H NMR (CDCl₃): δ ppm 7.64 (d, 1H, J=1.8 Hz, H-3), 7.57 (dd, 1H, J=1.8,8.2 Hz, H-5), 7.13 (d, 1H, J=8.2 Hz, H-6), 3.90 (s, 3H, OCH₃), 3.74 (s,2H, SCH₂CO), 2.34 (s, 3H, COCH₃), 2.15 (s, 3H, SCH₃).

Reference Example 4 Preparation of Intermediate (4):4-[2-chloro-2-(methylthio)acetyl]-2-methoxy phenyl acetate (4)

As shown in the above-described reaction formula, the mixture of 10 mlof carbon tetrachloride and 251 mg of N-chlorosuccinimide (1.88 mM) wasadded to 478 mg of 2-methoxy-4-[-2-(methylthio)acetyl]phenyl acetate(1.88 mM) at 0□. The mixture solution was left alone at room temperatureand stirred for 6 hours. The resulting product was filtrated and theremaining solvent was removed. The remaining residue was performed toSilica gel column chromatography with a mobile phase(n-hexane:ethylacetate=4:1) to obtain colorless oil type of4-[2-chloro-2-(methylthio)acetyl]-2-methoxy phenyl acetate (4; 542 mg).

Yield: 87%;

¹H NMR (CDCl₃): δ ppm 7.65 (d, 1H, J=2 Hz, H-3), 7.61 (dd, 1H, J=2, 8.2Hz, H-5), 7.14 (d, 1H, J=8.2 Hz, H-6), 6.31 (s, 1H, SCHCl), 3.90 (s, 3H,OCH₃), 2.34 (s, 3H, COCH₃), 2.24 (s, 3H, SCH₃).

Example 1 Methyl 2-[2-(4′ acetyloxy-3′methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetate (5a)

1.17 g of zinc chloride (18.6 mM) was added to the mixture of 7.8 mlphenol dissolved in 40 ml of dichloromethane and 2.25 g of4-[2-chloro-2-(methylthio)acetyl]-2-methoxy phenyl acetate (7.8 mM)under nitrogen gas atmosphere at −5° C.

The reaction mixture was stirred for 1 hour at −5° C. and cooled withadding water thereto slowly. The resulting product was filtrated and theremaining solvent was removed. The remaining residue was performed toSilica gel column chromatography with a mobile phase(n-hexane:ethylacetate=4:1) to obtain white solid type of Methyl2-[2-(4′-acetyloxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetate(5a; 3.12 g).

Yield: 81%;

m.p: 103° C.;

¹H NMR (CDCl₃): δ ppm 8.02 (d, 1H, J=1.8 Hz, H-2′), 7.93 (dd, 1H, J=1.8,8.4 Hz, H-6), 7.61 (d, 1H, J=1.3 Hz, H-4), 7.47 (d, 1H, J=8.4 Hz, H-5′,7.26 (dd, 1H, J=1.3, 8.2 Hz, H-6), 7.15 (d, 1H, J=8.2 Hz, H-7), 3.95 (s,3H, OCH₃), 3.77 (s, 2H, CH₂Ar), 3.72 (s, 3H, CO₂CH₃), 2.39 (s, 3H,COCH₃), 2.36 (s, 3H, SCH₃);

IR(KBr): δ ppm 2950, 1737, 1504, 1466, 1368, 1244, 1201, 1167, 1022cm⁻¹;

MS (EI) m/z 400 [M⁺].

Example 2 Methyl3-[2-(4′-acetyloxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionate(5b)

Through similar procedure to the method disclosed in Example 1, whitesolid type of methyl3-[2-(4′-acetyloxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5yl]propionate(5b; 9.87 g) showing following physicochemical property was obtained(yield: 84%).

m.p: 105° C.;

¹H NMR (CDCl₃): δ ppm 8.01 (d, 1H, J=1.8 Hz, H-2′), 7.92 (dd, 1H, J=1.8,8.4 Hz, H-6), 7.53 (d, 1H, J=1.8 Hz, H-4), 7.42 (d, 1H, J=8.4 Hz, H-5),7.18 (dd, 1H, J=1.8, 8.4 Hz, H-6), 7.14 (d, 1H, J=8.4 Hz, H-7), 3.95 (s,3H, OCH₃), 3.69 (s, 3H, CO₂CH₃), 3.09 (t, 2H, J=7.5 Hz, MeO₂CCH₂), 2.71(t, 2H, J=7.5 Hz, CH₂Ar), 2.38 (s, 3H, COCH₃), 2.35 (s, 3H, SCH₃);

IR (KBr): δ ppm 2947, 1764, 1736, 1601, 1500, 1468, 1369, 1242, 199,1168, 1031 cm⁻¹;

MS (EI) m/z 414 [M⁺].

Example 3 Methyl2-[2-(4′-acetyloxy-3′-methoxyphenyl)-1-benzofuran-5-yl]acetate (6a)

305 mg of2-[2-(4′-acetyloxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetate(5a; 0.76 mM) dissolved in 2 ml of ethanol was reacted with Raney nickelfor 2 hours at 60-65° C. The remaining agent was removed with filtrationand then the solvent was removed.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of methyl2-[2-(4′-acetyloxy-3′-methoxyphenyl)-1-benzofuran-5yl]acetate (6a; 269mg).

Yield: 92%;

m.p.: 99.9° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.20 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.11 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 3.95 (s, 3H,OCH₃), 3.72 (s, 2H, CH₂Ar), 3.71 (s, 3H, CO₂CH₃), 2.34 (s, 3H, COCH₃);

IR (KBr): δ ppm 1765, 1736, 1507, 1469, 1368, 1246, 1196, 1166, 1021cm⁻¹;

MS (FAB) m/z 354 [M⁺].

Example 4 Methyl3-[2-(4′-acetyloxy-3′-methoxyphenyl)-benzofuran-5-yl]propionate (6b)

Through similar procedure to the method disclosed in Example 3, whitesolid type of methyl3-[2-(4′-acetyloxy-3′-methoxyphenyl)-benzofuran-5-yl]propionate (6b;8.62 g) showing following physicochemical property was obtained (yield:94%).

m.p: 101.1° C.;

¹H NMR (CDCl₃): δ ppm 7.38-7.46 (m, 4H, Ar), 7.13 (dd, 1H, J=1.8, 8 Hz,H-6), 7.10 (d, 1H, J=8 Hz, H-7), 6.94 (d, 1H, J=0.9 Hz, H-3), 3.94 (s,3H, OCH₃), 3.68 (s, 3H, CO₂CH₃), 3.05 (t, 2H, J=7.8 Hz, MeO₂CCH₂), 2.68(t, 2H, J=7.8 Hz, CH₂Ar), 2.34 (s, 3H, COCH₃); IR (KBr): δ ppm 1765,1735, 1607, 1505, 1470, 1245, 1196, 1121, 1028 cm⁻¹;

MS (EI) m/z 368 [M⁺].

Example 52-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-1-benzofuran-5-yl]acetate(7a)

7.58 g of2-[2-(4′-acetyloxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetate(5a; 18.92 mM) dissolved in 200 ml of THF was reacted with 100 ml of 1Nlithium hydroxide. The reaction mixture was stirred for 2 hours at roomtemperature and the reacted product was acidified with dilutedhydrochloric acid salt. The resulting product was extracted withethylacetate, dried with anhydrous magnesium sulfate and the remainingsolvent was removed.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-1-benzofuran-5-yl]acetate(7a; 6.50 g).

Yield: 99%;

m.p: 197° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6), 7.59 (d, 1H, J=1.8Hz, H-4), 7.46 (d, 1H, J=8.3 Hz, H-5), 7.23 (dd, 1H, J=1.8, 8.3 Hz,H-6), 7.03 (d, 1H, J=8.3 Hz, H-7), 4.01 (s, 3H, OCH₃), 3.80 (s, 2H,CH₂Ar), 2.36 (s, 3H, SCH₃);

IR (KBr): δ ppm 3533, 3433, 1698, 1511, 1443, 1281, 1194, 1068 cm⁻¹; MS(EI) m/z 344 [M⁺].

Example 63-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionate(7b)

Through similar procedure to the method disclosed in Example 5, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionate(7b; 3.84 g) showing following physicochemical property was obtained(yield: 94%).

m.p: 163.3° C.;

¹H NMR (CDCl₃): δ ppm 7.84-7.9 (m, 2H, H-2′ and H-6′), 7.52 (d, 1H,J=1.7 Hz, H-4), 7.41 (d, 1H, J=8.4 Hz, H-5), 7.16 (dd, 1H, J=1.7, 8.4Hz, H-6), 7.03 (d, 1H, J=8.4 Hz, H-7), 4.01 (s, 3H, OCH₃), 3.10 (t, 2H,J=7.7 Hz, HO₂CCH₂) 2.77 (t, 2H, J=7.7 Hz, CH₂Ar), 2.36 (s, 3H, SCH₃);

IR (KBr): δ ppm 3470, 2921, 1717, 1605, 1508, 1473, 1443, 1278, 1203,1021 cm⁻¹;

MS (EI) m/z 358 [M⁺].

Example 7 2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]acetate(8a)

Through similar procedure to the method disclosed in Example 5, whitesolid type of 2-[2-(4′ hydroxy-3′ methoxyphenyl)-benzofuran-5-yl]acetate(8a; 2.60 g) showing following physicochemical property was obtained(yield: 95%).

m.p: 111.5° C.;

¹H NMR (CDCl₃): δ ppm 7.28-7.45 (m, 4H, Ar), 6.81-6.85 (m, 2H, H-3 andH-7), 6.75 (dd, 1H, J=1.8, 8.2 Hz, H-6), 5.14 (s, 1H, OH), 3.88 (s, 3H,OCH₃), 3.58 (s, 2H, CH₂Ar);

IR (KBr): δ ppm 3433, 1703, 1518, 1461, 1413, 1330, 1264, 1224, 1139,1025 cm⁻¹;

MS (FAB) m/z 298 [M⁺]

Example 8 3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]propionicacid (8b)

Through similar procedure to the method disclosed in Example 5, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]propionic acid (8b;1.73 g) showing following physicochemical property was obtained (yield:99%).

m.p.: 187.8° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.10 (dd, 1H, J=1.3, 8.3Hz, H-7), 6.99 (d, 1H, J=8.1 Hz, H-3), 6.83 (s, 1H, H-6), 5.75 (s, 1H,OH), 4.01 (s, 3H, OCH₃), 3.06 (t, 2H, J=7.7 Hz, HO₂CCH₂), 2.74 (t, 2H,J=7.7 Hz, CH₂Ar);

IR (KBr): δ ppm 3420, 1692, 1506, 1429, 1255, 1214, 1119, 1018 cm⁻¹; MS(EI) m/z 312 [M⁺].

Example 9Methyl-2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetate(9a)

The solution containing 98 mg of potassium carbonate (0.71 mM) dissolvedin 2 ml of water was added to the solution containing 195.6 mg of212-(4′-acetyloxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)acetate(5a; 0.47 mM) dissolved in 5 ml of methanol at 0□. The reaction mixturewas left alone at room temperature and stirred for 1 hour. The remainingsolvent was removed. The resulting product was extracted withethylacetate, dried with anhydrous magnesium sulfate and the remainingsolvent was removed.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of methyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetate(9a; 254 mg).

Yield: 94%;

m.p: 197° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6), 7.58 (d, 1H, J=1.8Hz, H-4), 7.44 (d, 1H, J=8.4 Hz, H-5, 7.23 (dd, 1H, J=1.8, 8.3 Hz, H-6),7.03 (d, 1H, J=8.3 Hz, H-7), 5.82 (s, 1H, OH), 4.01 (s, 3H, OCH₃), 3.76(s, 2H, CH₂Ar), 3.72 (s, 3H, CO₂CH₃), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3430, 1735, 1607, 1505, 1468, 1257, 1202, 1027 cm⁻¹; MS(FAB) m/z 359 [MH⁺].

Example 10Methyl-3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionate(9b)

Through similar procedure to the method disclosed in Example 9, whitesolid type of methyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionate(9b; 1.73 g) showing following physicochemical property was obtained(yield: 93%).

m.p: 82.8° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6), 7.50 (d, 1H, J=1.8Hz, H-4), 7.40 (d, 1H, J=8.4 Hz, H-5′, 7.15 (dd, 1H, J=1.8, 8.4 Hz,H-6), 7.02 (d, 1H, J=8.4 Hz, H-7), 5.81 (s, 1H, OH), 4.01 (s, 3H, OCH₃),3.69 (s, 3H, CO₂CH₃), 3.09 (t, 2H, J=7.5 Hz, MeO₂CCH₂), 2.71 (t, 2H,J=7.5 Hz, CH₂Ar), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3433, 2924, 1733, 1601, 1504, 1467, 1256, 1201, 1030cm⁻¹;

MS (FAB) m/z 372 [MH⁺]

Example 11 Methyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]acetate (10a)

Through similar procedure to the method disclosed in Example 9, whitesolid type of methyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]acetate (10a; 265 mg)showing following physicochemical property was obtained (yield: 95%).

m.p: 132° C.;

¹H NMR (CDCl₃): δ ppm 7.34-7.45 (m, 4H, Ar), 7.15 (dd, 1H, J=1.7, 8.2Hz, H-6), 6.98 (d, 1H, J=8.2 Hz, H-7), 6.83 (s, 1H, H-3), 3.99 (s, 3H,OCH₃), 3.70 (bs, 5H, CO₂CH₃ and CH₂Ar);

IR (KBr): δ ppm 3401, 2952, 1727, 1607, 1509, 1446, 1261, 1199, 1031cm⁻¹;

MS (FAB) m/z 313 [MH⁺].

Example 12 Methyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]propionate (10b)

Through similar procedure to the method disclosed in Example 9, whitesolid type of methyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]propionate (10b; 325mg) showing following physicochemical property was obtained (yield:92%).

m.p.: 124.0° C.;

¹H NMR (CDCl₃): δ ppm 7.34-7.42 (m, 4H, Ar), 7.08 (dd, 1H, J=1.7, 8 Hz,H-6), 6.98 (d, 1H, J=8 Hz, H-7), 6.83 (s, 1H, H-3), 5.75 (s, 1H, OH),4.00 (s, 3H, OCH₃), 3.68 (s, 3H, CO₂CH₃), 3.04 (t, 2H, J=7.8 Hz,MeO₂CCH₂), 2.68 (t, 2H, J=7.8 Hz, CH₂Ar);

IR (KBr): δ ppm 3435, 1718, 1606, 1508, 1442, 1374, 1262, 1199, 1032cm⁻¹;

MS (EI) m/z 326 [M⁺].

Example 132-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-ethanol(11a)

The suspension solution containing 68 mg of LAH (Lithium aluminumhydride; 1.8 m) dissolved in 1 ml of THF was added to the solutioncontaining 300 mg of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetate(9a; 1.8 mM) dissolved in 1 ml of THF. The reaction mixture was leftalone at room temperature and stirred for 5 hours. The reacted productwas cooled by adding 15 ml of water and 15 ml of 10% sulfuric acidslowly, extracted with diethyl ether, dried with anhydrous magnesiumsulfate and the remaining solvent was removed.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-ethanol(11a; 237 mg).

Yield: 55%;

m.p: 162.4° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6), 7.54 (d, 1H, J=1.8Hz, H-4), 7.44 (d, 1H, J=8.3 Hz, H-5′), 7.17 (dd, 1H, J=1.8, 8.1 Hz,H-6), 7.03 (d, 1H, J=8.1 Hz, H-7), 4.01 (s, 3H, OCH₃), 3.93 (t, 2H,J=6.5 Hz, HOCH₂), 3.01 (t, 2H, J=6.5 Hz, CH₂Ar) 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3398, 2948, 1600, 1499, 1463, 1405, 1287, 1236, 1130,1085, 1026 cm⁻¹;

MS (FAB) m/z 331 [MH⁺].

Example 143-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propanol(11b)

Through similar procedure to the method disclosed in Example 13, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propanol(11b; 650 mg) showing following physicochemical property was obtained(yield: 51%).

m.p.: 106° C.;

¹H NMR (CDCl₃): δ ppm 7.75-7.82 (m, 2H, H-2′ and H-6′), 7.42 (d, 1H,J=1.8 Hz, H-4), 7.32 (d, 1H, J=8.4 Hz, H-5′), 7.06 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.94 (d, 1H, J=8.4 Hz, H-7), 5.21 (s, 1H, OH), 3.92 (s, 3H,OCH₃), 3.64 (t, 2H, J=6.4 Hz, HOCH₂), 2.77 (t, 2H, J=7.5 Hz, CH₂Ar),2.29 (s, 3H, SCH₃), 1.84-1.97 (m, 2H, HOCH₂CH₂);

IR (KBr): δ ppm 3393, 2936, 1602, 1505, 1467, 1277, 1127, 1034 cm⁻¹;

MS (FAB) m/z 344 [MH⁺].

Example 15 2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-1-ethanol(12a)

Through similar procedure to the method disclosed in Example 13, whitesolid type of2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-1-ethanol (12a; 365mg) showing following physicochemical property was obtained (yield:58%).

m.p.: 171.6° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.46 (m, 4H, Ar), 7.11 (dd, 1H, J=1.7, 8.2Hz, H-6), 6.99 (d, 1H, J=8.2 Hz, H-7), 6.84 (s, 1H, H-3), 4.01 (s, 3H,OCH₃), 3.90 (t, 2H, J=6.5 Hz, HOCH₂), 2.96 (t, 2H, J=6.5 Hz, CH₂Ar);

IR (KBr): δ ppm 3431, 2952, 1732, 1608, 1510, 1469, 1261, 1201, 1024cm⁻¹;

MS (FAB) m/z 285 [MH⁺].

Example 163-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-1-propanol (12b)

Through similar procedure to the method disclosed in Example 13, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]-1-propanol (12b; 410mg) showing following physicochemical property was obtained (yield:53%).

m.p.: 156.6° C.;

¹H NMR (CD₃OD): δ ppm 7.22-7.32 (m, 4H, Ar), 6.98 (dd, 1H, J=1.7, 8.3Hz), 6.81 (d, 1H, J=0.7 Hz, H-3), 6.77 (d, 1H, J=8.3 Hz, H-7), 3.83 (s,3H, OCH₃), 3.49 (t, 2H, J=6.4 Hz, HOCH₂), 2.65 (t, 2H, J=7.5 Hz, CH₂Ar),1.72-1.82 (dt, 2H, HOCH₂CH₂);

IR (KBr): δ ppm 3444, 3123, 2932, 1606, 1514, 1419, 1276, 1239, 1130,1047 cm⁻¹;

MS (EI) m/z 298 [M⁺].

Example 172-[2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanol(13a)

650 mg of potassium carbonate (4.70 mM) and 329 mg of chloromethylmethyl ether (4.09 mM) were added to the solution containing 670 mg of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-ethanol(11a; 2.03 mM) dissolved in 35 ml of acetone. The reaction mixture wasperformed to reflux distillation for 4 hours and cooled to roomtemperature. The remaining potassium carbonate was removed withfiltration and washing process and the filtrate was concentrated withvaccuo.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of2-[2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanol(13a; 605 mg).

Yield: 80%;

m.p.: 80-82° C.;

¹H NMR (CDCl₃): δ ppm 7.95 (d, 1H, J=1.8 Hz), 7.88 (dd, 1H, J=8.4, 2.0Hz), 7.55 (d, 1H), 7.45 (d, 1H, J=8.3 Hz), 7.26 (d, 1H, J=8.6 Hz), 7.19(dd, 1H, J=8.4, 1.4 Hz), 5.31 (s, 2H), 4.00 (s, 3H), 3.94 (m, 2H), 3.55(s, 3H), 3.02 (t, 2H, J=6.1 Hz), 2.38 (s, 3H);

IR (KBr): δ ppm 3399, 2922, 1504, 1468, 1245, 1136, 1079, 990 cm⁻¹.

Example 183-[2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-1-propan-1-ol(13b)

Through similar procedure to the method disclosed in Example 13, whitesolid type of3-[2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-1-propan-1-ol(13b; 1.97 g) showing following physicochemical property was obtained(yield: 91%).

m.p.: 60˜64° C.;

¹H NMR (CD₃OD): δ ppm 7.94 (d, 1H, J=2.0 Hz), 7.87 (dd, 1H, J=8.4, 2.0Hz), 7.51 (d, 1H), 7.42 (d, 1H, J=8.2 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.16(dd, 1H, J=8.4, 1.7 Hz), 5.31 (s, 2H), 4.00 (s, 3H), 3.75 (m, 2H), 3.55(s, 3H), 2.86 (t, 2H, J=7.5 Hz), 2.38 (s, 3H), 1.98 (m, 2H);

IR (KBr): δ ppm 3396, 2924, 1504, 1468, 1245, 1136, 1079, 990 cm⁻¹.

Example 195-(2-methoxy-ethyl)-2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran(14a)

642 mg of hydride substance (16.1 mM) and 2.26 g of iodomethane (15.9mM) were added to the solution containing 595 mg of2-[2-(3-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanol(13a; 1.59 mM) dissolved in 40 ml of THF. The reaction mixture wasperformed to reflux distillation for 16 hours and cooled to roomtemperature. The reaction mixture was extracted with 50 ml of water andethylacetate to divide into water layer and organic solvent layer. Theorganic solvent layer was dried with magnesium sulfuric acid, filtratedand the filtrate was concentrated with vaccuo.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of5-(2-methoxy-ethyl)-2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran(14a; 410 mg).

Yield: 99%;

m.p.: 70° C.;

¹H NMR (CDCl₃): δ ppm 7.94 (d, 1H, J=2.01 Hz) 7.87 (dd, 1H, J=8.07 Hz &J=2.01 Hz), 7.53 (s, 1H,) 7.42 (d, 1H, J=8.43 Hz,), 7.26 (m, 1H) 7.19(d, 1H, J=8.43 Hz, 5.29 (s, 2H), 4.0 (s, 3H), 3.67 (t, 2H, J=7.14 Hz),3.55 (s, 3H), 3.39 (s, 3H), 3.02 (t, 2H, J=6.6 Hz), 2.38 (s, 3H);

IR (KBr): δ ppm 2923, 1736, 1605, 1504, 1467, 1245, 1114, 1080, 993,886, 809 cm⁻¹;

MS (FAB+) m/z 388[M⁺].

Example 202-(3-methoxy-4-methoxymethoxy-phenyl)-5-(3-methoxy-propyl)-3-methylsulfanyl-benzofuran(14b)

Through similar procedure to the method disclosed in Example 19, whitesolid type of2-(3-methoxy-4-methoxymethoxy-phenyl)-5-(3-methoxy-propyl)-3-methylsulfanyl-benzofuran(14b; 1.86 g) showing following physicochemical property was obtained(yield: 96%).

m.p: 50˜52° C.;

¹H NMR (CDCl₃): δ ppm 7.94 (d, 1H, J=2.0 Hz), 7.87 (dd, 1H, J=8.6, 2.0Hz), 7.51 (d, 1H), 7.42 (d, 1H, J=8.3 Hz), 7.26 (d, 1H, J=8.4 Hz), 7.15(dd, 1H, J=8.2, 1.7 Hz), 5.31 (s, 2H), 4.00 (s, 3H), 3.55 (s, 3H), 3.43(t, 2H, J=6.4 Hz), 3.37 (s, 3H), 2.83 (t, 2H, J=7.3 Hz), 2.38 (s, 3H),2.01-1.92 (m, 2H);

IR (KBr): δ ppm 2924, 1504, 1468, 1246, 1133, 1080, 992 cm⁻¹;

MS (FAB+) m/z 402[M⁺].

Example 212-methoxy-4-[5-(2-methoxy-ethyl)-3-methylsulfanyl-benzofuran-2-yl]-phenol(15a)

The solution containing 590 mg of5-(2-methoxy-ethyl)-2-(3-methoxy-4-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran(14a; 1.52 mM) dissolved in 8 ml of dichloromethane was cooled to 0□.4.0 ml of trifluoroacetic acid was added thereto and stirred for 40 minsat 0□. 7.5 g of solid sodium hydrogen carbonate and 60 ml of water wereadded thereto slowly at 0□. The reaction mixture was extracted withdichloromethane. The organic solvent layer was dried with magnesiumsulfuric acid, filtrated and the filtrate was concentrated with vaccuo.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of2-methoxy-4-[5-(2-methoxy-ethyl)-3-methylsulfanyl-benzofuran-2-yl]-phenol(15a; 455 mg).

Yield: 87%;

m.p.: 67° C.;

¹H NMR (CDCl₃): δ ppm 7.87-7.84 (m, 2H), 7.52 (d, 1H, J=1.29 Hz), 7.40(d, 1H, J=8.25 Hz), 7.16 (dd, 1H, J=8.4 & 1.65 Hz), 7.01 (d, 1H,J=8.07), 6.0 (s, 1H), 3.98 (s, 3H), 3.67 (t, 2H, J=7.14 Hz), 3.39 (s,3H), 3.02 (t, 2H, J=6.96), 2.37 (s, 3H);

IR (KBr): δ ppm 3398, 2923, 1603, 1505, 1468, 1256, 1200, 1113, 1033,969, 861, 813 cm⁻¹;

MS (FAB+) m/z 344 [M⁺].

Example 222-methoxy-4-[5-(3-methoxy-propyl)-3-methylsulfanyl-benzofuran-2-yl]-phenol(15b)

Through similar procedure to the method disclosed in Example 21, whitesolid type of2-methoxy-4-[5-(3-methoxy-propyl)-3-methylsulfanyl-benzofuran-2yl]-phenol(15b; 1.22 g) showing following physicochemical property was obtained(yield: 75%).

m.p.: 57˜59° C.;

¹H NMR (CDCl₃): δ ppm 7.88˜7.85 (m, 2H), 7.49 (d, 1H), 7.40 (d, 1H,J=8.3 Hz,), 7.14 (dd, 1H, J=8.3, 1.8 Hz), 7.03 (d, 1H, J=8.4 Hz), 5.82(s, OH), 4.01 (s, 3H), 3.43 (t, 2H, J=6.4 Hz), 3.37 (s, 3H), 2.82 (t,2H, J=7.4 Hz), 2.37 (s, 3H), 2.01-1.92 (m, 2H);

IR (KBr): δ ppm 3396, 2923, 1505, 1468, 1256, 1201, 1118 cm⁻¹;

MS (FAB+) m/z 358 [M⁺].

Example 23 2-methoxy-4-[5-(2-methoxy-ethyl)-benzofuran-2-yl]-phenol(16a)

Through similar procedure to the method disclosed in Example 3, whitesolid type of 2-methoxy-4-[5-(2-methoxy-ethyl)-benzofuran-2-yl]-phenol(16a; 330 mg) showing following physicochemical property was obtained(yield: 94%).

m.p: 180° C.;

¹H NMR (CDCl₃): δ ppm d 7.87-7.84 (m, 2H), 7.52 (d, 1H, J=1.29 Hz), 7.40(d, 1H, J=8.25 Hz), 7.16 (dd, 1H, J=8.4 & 1.65 Hz), 7.01 (d, 1H, J=8.07Hz), 6.0 (s, 1H), 3.98 (s, 3H), 3.67 (t, 2H, J=7.14), 3.39 (s, 3H), 3.02(t, 2H, J=6.96 Hz), 2.37 (s, 3H);

IR (KBr): δ ppm 3395, 2928, 1725, 1609, 1509, 1469, 1257, 1200, 1116,1030, 995, 862, 805 cm⁻¹;

MS (FAB+) m/z 298 [M⁺].

Example 24 2-methoxy-4-[5-(3-methoxy-propyl)-benzofuran-2-yl]-phenol(16b)

Through similar procedure to the method disclosed in Example 21, whitesolid type of 2-methoxy-4-[5-(3-methoxy-propyl)-benzofuran-2-yl]-phenol(16b; 750 mg) showing following physicochemical property was obtained(yield: 96%).

m.p.: 76˜78° C.;

¹H NMR (CDCl₃): δ ppm 7.41-7.36 (m, 4H), 7.09 (dd, 1H), 6.98 (d, 1H,J=8.0 Hz), 6.83 (s, 1H), 5.75 (s, OH), 4.00 (s, 3H), 3.41 (t, 2H, J=6.4Hz), 3.36 (s, 3H), 2.78 (t, 2H, J=7.0 Hz), 1.98-1.91 (m, 2H);

IR (KBr): δ ppm 3396, 2925, 1609, 1510, 1469, 1257, 1201, 1119 cm⁻¹;

MS (FAB+) m/z 312 [M⁺].

Example 252-(3,4-dimethoxy-phenyl)-5-(2-methoxy-ethyl)-3-methylsulfanyl-benzofuran(17a)

Through similar procedure to the method disclosed in Example 19, whitesolid type of2-(3,4-dimethoxy-phenyl)-5-(2-methoxy-ethyl)-3-methylsulfanyl-benzofuran(17a; 674 mg) showing following physicochemical property was obtained(yield: 93.3%).

m.p.: 61° C.;

¹H NMR (CDCl₃): δ ppm 7.92 (s, 1H), 7.89 (d, 1H, J=2.0 Hz), 7.53 (s,1H), 7.42 (d, 1H, J=8.22 Hz), 7.17 (dd, 1H, J=8.43 & 2.01 Hz), 6.98 (d,1H, J=8.04), 4.0 (s, 3H), 3.96 (s, 3H), 3.67 (t, 2H, J=7.14 Hz), 3.39(s, 3H), 3.02 (t, 2H, J=6.96 Hz), 2.38 (s, 3H);

IR (KBr): δ ppm 2923, 2855, 1507, 1464, 1255, 1144, 1113, 1027, 807cm⁻¹;

MS (FAB+) m/z 358 [M⁺].

Example 262-(3,4-dimethoxy-phenyl)-5-(3-methoxy-propyl)-3-methylsulfanyl-benzofuran(17b)

Through similar procedure to the method disclosed in Example 19, whitesolid type of2-(3,4-dimethoxy-phenyl)-5-(3-methoxy-propyl)-3-methylsulfanyl-benzofuran(17b; 3.75 g) showing following physicochemical property was obtained(yield: 99.5%).

m.p.: 68˜70° C.;

¹H NMR (CDCl₃): δ ppm 7.92-7.89 (m, 2H), 7.50 (s, 1H), 7.41 (d, 1H,J=8.4 Hz), 7.15 (d, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8.5 Hz), 4.01 (s, 3H),3.96 (s, 3H), 3.43 (t, 2H, J=6.2 Hz), 3.37 (s, 3H), 2.83 (t, 2H, J=7.5Hz), 2.38 (s, 3H), 1.97 (m, 2H);

IR (KBr): δ ppm 2925, 1605, 1506, 1467, 1254, 1145, 1118, 1027 cm⁻¹;

MS (FAB+) m/z 372 [M⁺].

Example 27 2-(3,4-dimethoxy-phenyl)-5-(2-methoxy-ethyl)-benzofuran (18a)

Through similar procedure to the method disclosed in Example 19, whitesolid type of 2-(3,4-dimethoxy-phenyl)-5-(2-methoxy-ethyl)-benzofuran(18a; 486 mg) showing following physicochemical property was obtained(yield: 95.3%).

m.p.: 81° C.;

¹H NMR (CDCl₃): δ ppm 7.43-7.36 (m, 4H), 7.14 (dd, 1H, J=8.25 & HzJ=1.65 Hz), 6.93 (d, 1H, J=8.43 Hz), 6.85 (s, 1H), 3.99 (s, 3H), 3.93(s, 3H), 3.64 (t, 2H, J=7.14 Hz), 3.38 (s, 3H), 2.97 (t, 2H, J=6.96 Hz);

IR (KBr): δ ppm 2924, 2855, 1730, 1608, 1511, 1463, 1377, 1255, 1115,1028, 861, 804 cm⁻¹;

MS (FAB+) m/z 312 [M⁺].

Example 28 2-(3,4-dimethoxy-phenyl)-5-(3-methoxy-propyl)-benzofuran(18b)

Through similar procedure to the method disclosed in Example 19, paleyellow solid type of2-(3,4-dimethoxy-phenyl)-5-(3-methoxy-propyl)-benzofuran (18b; 2.65 g)showing following physicochemical property was obtained (yield: 97.7%).

m.p: 93˜95° C.;

¹H NMR (CDCl₃): δ ppm 7.45-7.36 (m, 4H), 7.09 (dd, 1H, J=8.3, 1.7 Hz),6.94 (d, 1H, J=8.6 Hz), 6.86 (d, 1H, J=0.7 Hz), 4.00 (s, 3H), 3.94 (s,3H), 3.41 (t, 2H, J=6.2 Hz), 3.36 (s, 3H), 2.78 (t, 2H, J=7.3 Hz),1.99-1.89 (m, 2H);

IR (KBr): δ ppm 2927, 1608, 1511, 1468, 1254, 1170, 1119, 1026 cm⁻¹; MS(FAB+) m/z 326

Example 29 Benzyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(19a)

Benzyl alcohol was added to the solution containing 128 mg of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-1-benzofuran-5-yl]acetate(7a; 0.37 mM) dissolved in 4 ml of dimethylformamide and the solutionwas cooled to 0□. 107 mg of ethylene dichloride (0.56 mM) was addedthereto and then dimethylaminopyridine was added thereto as a catalyst.The solution was heated for overnight at 120□. The reaction mixture wasextracted with diethylether. The organic solvent layer was dried withmagnesium sulfuric acid, filtrated and the filtrate was concentratedwith vaccuo.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of benzyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(19a; 160 mg).

Yield: 98%;

m.p: 94.2° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.60 (d, 1H,J=1.8 Hz, H-4), 7.44 (d, 1H, J=8.4 Hz, H-5′, 7.3°). 4 (m, 5H, Ph), 7.23(dd, 1H, J=1.8, 8.4 Hz, H-6), 7.03 (d, 1H, J=8.4 Hz, H-7), 5.83 (s, 1H,OH), 5.16 (s, 2H, PhCH₂CO), 4.01 (s, 3H, OCH₃), 3.80 (s, 2H, CH₂Ar),2.34 (s, 3H, SCH₃);

IR (KBr): δ ppm 3443, 2924, 1732, 1602, 1505, 1467, 1257, 1080, 1029cm⁻¹;

MS (FAB) m/z 435 [MH⁺].

Example 30 Benzyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5yl]propionate(19b)

Through similar procedure to the method disclosed in Example 29, whitesolid type of benzyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5yl]propionate(19b; 145 mg) showing following physicochemical property was obtained(yield: 97%).

m.p: 87° C.;

¹H NMR (CDCl₃): δ ppm 7.84-7.9 (m, 2H, H-2′ and H-6′), 7.49 (d, 1H,J=1.8 Hz, H-4), 7.38 (d, 1H, J=8.4 Hz, H-5′, 7.3-7.4 (m, 5H, Ph), 7.13(dd, 1H, J=1.8, 8 Hz, H-6), 7.02 (d, 1H, J=8 Hz, H-7), 5.82 (s, 1H, OH),5.12 (s, 2H, PhCH₂CO), 4.01 (s, 3H, OCH₃), 3.11 (t, 2H, J=7.7 Hz,MeO₂CCH₂), 2.76 (t, 2H, J=7.7 Hz, CH₂Ar), 2.34 (s, 3H, SCH₃);

IR (KBr): δ ppm 3397, 2928, 1732, 1649, 1506, 1462, 1258, 1080, 1030cm⁻¹;

MS (FAB) m/z 449 [MH⁺].

Example 31 pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a)

95.55 mg of pentafluorophenol (0.52 mM) was added to the solutioncontaining 154.7 mg of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-1-benzofuran-5-yl]acetate(7a; 0.52 mM) dissolved in 2 ml of dichloromethane added with 2 drops ofdimethylformamide and the solution was cooled to 0□. 107 mg of ethylenedichloride (0.56 mM) was added thereto and then the solution was leftalone at room temperature. The reaction mixture was extracted withdichloromethane. The organic solvent layer was dried with magnesiumsulfuric acid, filtrated and the filtrate was concentrated with vaccuo.

The remaining residue was purified with Silica gel column chromatographywith a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solidtype of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 241 mg).

Yield: 81%;

m.p: 109° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.92 (m, 2H, H-2′ and H-6′), 7.67 (d, 1H,J=1.8 Hz, H-4), 7.50 (d, 1H, J=8.3 Hz, H-5′), 7.28 (dd, 1H, J=1.8, 7.9Hz, H-6), 7.04 (d, 1H, J=7.9 Hz, H-7), 5.83 (s, 1H, OH), 4.10 (s, 3H,OCH₃), 4.02 (s, 2H, ArO₂CCH₂), 2.38 (s, 3H, SCH₃).

Example 32 Pentafluorophenyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionate(20b)

Through similar procedure to the method disclosed in Example 31, whitesolid type of Pentafluorophenyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionate(20b; 180 mg) showing following physicochemical property was obtained(yield: 85%).

m.p: 141° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.92 (m, 2H, H-2′ and H-6′), 7.56 (d, 1H,J=1.8 Hz, H-4), 7.44 (d, 1H, J=8.2 Hz, H-5′), 7.19 (dd, 1H, J=1.8, 8.3Hz, H-6), 7.03 (d, 1H, J=8.3 Hz, H-7), 4.01 (s, 3H, OCH₃), 3.23 (t, 2H,J=7.4 Hz, ArO₂CCH₂), 3.07 (t, 2H, J=7.4 Hz, CH₂Ar), 2.37 (s, 3H, SCH₃).

Example 33 Pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]acetate (21a)

Through similar procedure to the method disclosed in Example 31, whitesolid type of Pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]acetate (21a; 684 mg)showing following physicochemical property was obtained (yield: 88%).

m.p: 140.2° C.;

¹H NMR (CDCl₃): δ ppm 7.54 (bs, 1H, H-2′), 7.50 (bd, 1H, H-6′),7.35-7.42 (m, 2H, H-5′ and H-4), 7.24 (dd, 1H, J=1.8, 8.3 Hz, H-6), 7.00(d, 1H, J=8.3 Hz, H-7), 6.88 (s, 1H, H-3), 5.76 (s, 1H, OH), 4.05 (s,2H, ArO₂CCH₂), 4.01 (s, 3H, OCH₃).

Example 34 Pentafluorophenyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]propionate (21b)

Through similar procedure to the method disclosed in Example 31, whitesolid type of Pentafluorophenyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-benzofuran-5-yl]propionate (21b; 1.21g) showing following physicochemical property was obtained (yield: 87%).

m.p: 138° C.;

¹H NMR (CDCl₃): δ ppm 7.35-7.46 (m, 4H, Ar), 7.13 (dd, 1H, J=1.7, 8.3Hz, H-6), 6.99 (d, 1H, J=8.3 Hz, H-7), 6.85 (s, 1H, H-3), 5.76 (s, 1H,OH), 4.01 (s, 3H, OCH₃), 3.18 (t, 2H, J=7.4 Hz, ArO₂CCH₂), 3.03 (t, 2H,J=7.4 Hz, CH₂Ar).

Example 35 N,N-diethyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22a)

0.06 ml of diethylamine (0.6 mM) was added to the solution containing213 mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.4 mM) dissolved in 0.6 ml of dichloromethane and the solutionwas cooled to 0° C. The reaction mixture was left alone at roomtemperature and stirred for 1 hour. The organic solvent was removed andthe remaining residue was purified with Silica gel column chromatographywith a mobile phase (dichloromethane:methanol=8:1) to obtain white solidtype of N,N-diethyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22a; 160 mg).

Yield: 65%;

m.p: 167° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.55 (d, 1H,J=1.5 Hz, H-4), 7.43 (d, 1H, J=8.1 Hz, H-5′), 7.22 (dd, 1H, J=1.5, 8.3Hz, H-6), 7.02 (d, 1H, J=8.3 Hz, H-7), 5.82 (s, 1H, OH), 4.01 (s, 3H,OCH₃), 3.83 (s, 2H, CH₂Ar), 3.39 (dq, 4H, (CH₃CH₂)₂N), 2.36 (s, 3H,SCH₃), 1.14 (dd, 6H, (CH₃CH₂)₂N);

IR (KBr): δ ppm 3427, 2482, 1646, 1502, 1469, 1243, 1162, 1006 cm⁻¹;

MS (FAB) m/z 400 [MH⁺].

Example 36 N,N-dimethyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22b)

2 N diethylamine dissolved in 0.2 ml of methanol (0.38 mM) was added tothe solution containing 127 mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.38 mM) dissolved in 2 ml of methanol cooled to −78° C. Thereaction mixture was heat at 80° C. and stirred for 2 hours. The organicsolvent was removed and the remaining residue was purified with Silicagel column chromatography with a mobile phase(dichloromethane:methanol=8:1) to obtain white solid type ofN,N-dimethyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22b; 92 mg).

Yield: 98%;

m.p: 134.9° C.;

¹H NMR (CDCl₃): δ ppm 7.83-7.9 (m, 2H, H-2′ and H-6′), 7.55 (d, 1H,J=1.8 Hz, H-4), 7.43 (d, 1H, J=8.4 Hz, H-5′), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.4 Hz, H-7), 5.89 (s, 1H, OH), 4.01 (s, 3H,OCH₃), 3.85 (s, 2H, CH₂Ar), 3.05 (s, 3H, (CH₃)₂N), 3.00 (s, 3H,(CH₃)₂N), 2.35 (s, 3H, SCH₃);

IR (KBr): δ ppm 2925, 1631, 1504, 1466, 1279, 1129, 1031 cm⁻¹;

MS (EI) m/z 371 [M⁺].

Example 37 N-methyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22c)

Through similar procedure to the method disclosed in Example 36, whitesolid type of N-methyl.2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22c; 157 mg) showing following physicochemical property was obtained(yield: 60%).

m.p: 157.5° C.;

¹H NMR (CDCl₃): δ ppm 7.86-7.9 (m, 2H, H-2′ and H-6′), 7.56 (d, 1H,J=1.8 Hz, H-4), 7.48 (d, 1H, J=8.4 Hz, H-5′), 7.19 (dd, 1H, J=1.8, 8.1Hz, H-6), 7.04 (d, 1H, J=8.1 Hz, H-7), 5.38 (bs, 1H, NH), 4.02 (s, 3H,OCH₃), 3.72 (s, 2H, CH₂Ar), 2.77 (d, 3H, J=4.95 Hz, CH₃NH), 2.37 (s, 3H,SCH₃);

IR (KBr): δ ppm 3742, 1646, 1507, 1465, 1279 cm⁻¹;

MS (EI) m/z 357 [M⁺].

Example 382-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-morpholino-1-ethanone(22d)

0.04 ml of morpholine (0.4 mM) was added to the solution containing 137mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.27 mM) dissolved in 2 ml of dichloromethane. The reactionmixture was stirred for 1 hour and the solvent was removed. Theremaining residue was purified with Silica gel column chromatographywith a mobile phase (dichloromethane:methanol=8:1) to obtain white solidtype of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-morpholino-1-ethanone(22d; 112 mg).

Yield: 55%;

m.p: 170.5° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.53 (d, 1H,J=1.5 Hz, H-4), 7.45 (d, 1H, J=8.4 Hz, H-5′), 7.19 (dd, 1H, J=1.5, 8 Hz,H-6), 7.02 (d, 1H, J=8 Hz, H-7), 5.84 (s, 1H, OH), 4.01 (s, 3H, OCH₃),3.86 (s, 2H, CH₂Ar), 3.67 (s, 4H, CH₂OCH₂), 3.50 (s, 4H, CH₂NCH₂), 2.35(s, 3H, SCH₃);

IR (KBr): δ ppm 3280, 2920, 1633, 1505, 1464, 1276, 1117, 1034 cm⁻¹;

MS (FAB) m/z 414 [MH⁺].

Example 392-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-piperazino-1-ethanone(22e)

0.09 ml of 1-benzyl piperazine (0.52 mM) was added to the solutioncontaining 17.88 mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.21 mM) dissolved in 1 ml of dimethyl sulfoxide. The reactionmixture was stirred for 10 minutes and the solvent was removed. Theremaining residue was purified with Silica gel column chromatographywith a mobile phase (dichloromethane:methanol=8:1) to obtain white solidtype of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-piperazino-1-ethanone(22e; 87 mg).

Yield: 63%;

m.p: 88.5° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H; H-2′ and H-6′), 7.54 (d, 1H, J=2Hz, H-4), 7.44 (d, 1H, J=8.4 Hz, H-5′), 7.20 (dd, 1H, J=2, 8.4 Hz, H-6),7.02 (d, 1H, J=8.4 Hz, H-7), 4.01 (s, 3H, OCH₃), 3.86 (s, 2H, CH₂Ar),3.67 (bt, 2H, CH₂N(C═O)CH₂), 3.49 (bt, 2H, CH₂N(C═O)CH₂), 2.85 (s, 2H,CH₂NHCH₂), 2.69 (s, 2H, CH₂NHCH₂), 2.35 (s, 3H, SCH₃);

IR (KBr): δ ppm 2921, 1631, 1504, 1463, 1279, 1127, 1030 cm⁻¹;

MS (FAB) m/z 413 [MH⁺].

Example 402-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperazino)-1-ethanone(22f)

0.09 ml of 1-benzyl piperazine (0.52 mM) was added to the solutioncontaining 132 mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.26 mM) dissolved in 2 ml of dichloromethane. The reactionmixture was stirred for 1 hour and the solvent was removed. Theremaining residue was purified with Silica gel column chromatographywith a mobile phase (dichloromethane:methanol=8:1) to obtain white solidtype of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperazino)-1-ethanone(22f; 130 mg).

Yield: 34%;

m.p: 69.1° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.52 (bs, 1H,H-4), 7.42 (d, 1H, J=8.4 Hz, H-5′), 7.24-7.3 (m, 5H, Ph), 7.17 (dd, 1H,J=1.8, 8 Hz, H-6), 7.02 (d, 1H, J=8 Hz, H-7), 4.01 (s, 3H, OCH₃), 3.85(s, 2H, CH₂Ar), 3.69 (bt, 2H, CH₂N(C═O)CH₂), 3.50 (bt, 2H,CH₂N(C═O)CH₂), 3.48 (s, 2H, PhCH₂N), 2.44 (s, 2H, CH₂NCH₂), 2.35 (s, 3H,SCH₃), 2.28 (s, 2H, CH₂NCH₂);

IR (KBr): δ ppm 2921, 1638, 1506, 1462, 1279, 1128 cm⁻¹;

MS (FAB) m/z 503 [MH⁺].

Example 412-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperidino)-1-ethanone(22 g)

0.035 ml of 4-benzyl piperidine (0.2 mM) was added to the solutioncontaining 103 mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.2 mM) dissolved in 2 ml of dichloromethane. The reaction mixturewas stirred for 30 mins and the solvent was removed. The remainingresidue was purified with Silica gel column chromatography with a mobilephase (dichloromethane:methanol=8:1) to obtain white solid type of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperidino)-1-ethanone(22 g; 101 mg).

Yield: 65%;

m.p: 206.8° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.53 (d, 1H,J=1.5 Hz, H-4), 7.42 (d, 1H, J=8.4 Hz, H-5′), 7.05-7.3 (m, 6H, Ph andH-6), 7.02 (d, 1H, J=8.4 Hz, H-7), 5.82 (bs, 1H, OH), 4.66 (m, 1H,CH₂NCH₂), 4.01 (s, 3H, OCH₃), 3.92 (m, 1H, CH₂NCH₂), 3.85 (s, 2H,CH₂Ar), 2.93 (m, 1H, CH₂NCH₂), 2.45-2.6 (m, 3H, CH₂NCH₂ and PhCH₂), 2.35(s, 3H, SCH₃), 1.58-1.72 (m, 4H, CH₂CH₂NCH₂CH₂), 0.9-1.3 (m, 1H, BnCH);

IR (KBr): δ ppm 2922, 1618, 1507, 1461, 1278, 1028 cm⁻¹;

MS (FAB) m/z 502 [MH⁺].

Example 42(R)-3-(2-[2-(4-hydroxy-3-methoxyphenyl)-3-(methylsulfanyl)-1-benzofuran-5-yl]acetylamino-4-methylpentanamide (22 h)

0.04 ml of triethylamine (0.4 mM) and 32 mg of L-Leucinamidehydrochloride (0.4 mM) was added to the solution containing 98.8 mg ofpentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.4 mM) dissolved in 2 ml of dimethylformamide. The reactionmixture was stirred for 30 mins and the solvent was removed. Theremaining residue was purified with Silica gel column chromatographywith a mobile phase (dichloromethane:methanol=8:1) to obtain white solidtype of(R)-3-(2-[2-(4-hydroxy-3-methoxyphenyl)-3-(methylsulfanyl)-1-benzofuran-5-yl]acetylamino-4-methylpentanamide (22 h; 91 mg).

Yield: 98%;

m.p: 220.1° C.;

¹H NMR (CD₃OD): δ ppm 7.94 (d, 1H, J=1.8 Hz, H-2′), 7.77 (dd, 1H, J=1.8,8.4 Hz, H-6′), 7.62 (d, 1H, J=1.5 Hz, H-4), 7.43 (d, 1H, J=8.4 Hz, H-5′,7.25 (dd, 1H, J=1.5, 8.4 Hz, H-6), 6.90 (d, 1H, J=8.4 Hz, H-7), 5.48(bs, 1H, OH), 4.41 (m, 1H, CHNH), 3.94 (s, 3H, OCH₃), 3.68 (dd of AB,2H, J=14, 21 Hz, CH₂Ar), 2.36 (s, 3H, SCH₃), 1.55-1.7 (m, 3H, CHMe₂ andCH₂CONH₂), 0.9 (dd, 6H, J=6, 16.5 Hz, CH(CH₃)₂);

IR (KBr): δ ppm 3855, 3742, 2955, 1651, 1541, 1509, 1464, 1278 cm⁻¹; MS(FAB) m/z 457 [MH⁺], 479 [MNa⁺].

Example 43 N-phenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22i)

0.05 ml of aniline (0.5 mM) was added to the solution containing 170.6mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.33 mM) dissolved in 5 ml of dichloromethane. The reactionmixture was heated at 65□, stirred for 2 hours and the solvent wasremoved. The remaining residue was purified with Silica gel columnchromatography with a mobile phase (dichloromethane:methanol=8:1) toobtain white solid type of N-phenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22i; 138 mg).

Yield: 40%;

m.p: 166.3° C.;

¹H NMR (CDCl₃): δ ppm 7.88-7.92 (m, 2H, H-2′ and H-6′), 7.64 (d, 1H,J=1.5 Hz, H-4), 7.52 (d, 1H, J=8.4 Hz, H-5′), 7.41 (d, 2H, Ph),7.26-7.30 (m, 2H, Ph and H-6), 7.09 (d, 2H, Ph), 7.04 (d, 1H, J=8.4 Hz,H-7), 5.85 (s, 1H, OH), 4.02 (s, 3H, OCH₃), 3.88 (s, 2H, CH₂Ar), 2.38(s, 3H, SCH₃);

IR (KBr): δ ppm 3435, 1658, 1505, 1464, 1278 cm⁻¹;

MS (EI) m/z 419 [M⁺].

Example 44 N-benzyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22j)

0.06 ml of benzylamine (0.53 mM) was added to the solution containing176.8 mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.35 mM) dissolved in 5 ml of dichloromethane. The reactionmixture was stirred for 1 hour and the solvent was removed. Theremaining residue was purified with Silica gel column chromatographywith a mobile phase (dichloromethane:methanol=8:1) to obtain white solidtype of N-benzyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(22j; 151 mg).

Yield: 61%;

m.p: 166.4° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.57 (d, 1H,J=1.5 Hz, H-4), 7.47 (d, 1H, J=8.3 Hz, H-5′), 7.17-7.4 (m, 6H, Ph andH-6), 7.03 (d, 1H, J=8 Hz, H-7), 5.74 (bt, 1H, NH), 4.44 (d, 2H, J=5.9Hz, PhCH₂NH), 4.01 (s, 3H, OCH₃), 3.77 (s, 2H, CH₂Ar), 2.34 (s, 3H,SCH₃);

IR (KBr): δ ppm 3855, 3741, 1644, 1505, 1463, 1277, 1029 cm⁻¹;

MS (FAB) m/z 434 [MH⁺].

Example 45 N,N-diethyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionamide(22k)

Through similar procedure to the method disclosed in Example 35, whitesolid type of N,N-diethyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionamide(22k; 140 mg) showing following physicochemical property was obtained(yield: 63%).

m.p: 108.4° C.;

¹H NMR (CDCl₃): δ ppm 7.84-7.9 (m, 2H, H-2′ and H-6′), 7.51 (d, 1H,J=1.5 Hz, H-4), 7.40 (d, 1H, J=8.2 Hz, H-5′), 7.17 (dd, 1H, J=1.7, 8.3Hz, H-6), 7.02 (d, 1H, J=8.3 Hz, H-7), 5.93 (s, 1H, OH), 4.01 (s, 3H,OCH₃), 3.39 (q, 2H, J=7.1 Hz, CH₃CH₂N), 3.24 (q, 2H, J=7.1 Hz, CH₃CH₂N),3.12 (t, 2H, J=7.9 Hz, >NCOCH₂), 2.67 (t, 2H, J=7.9 Hz, CH₂Ar), 2.37 (s,3H, SCH₃), 1.12 (dt, 6H, (CH₃CH₂)₂N);

IR (KBr): δ ppm 2974, 1617, 1504, 1466, 1279, 1129, 1081, 1032 cm⁻¹;

MS (FAB) m/z 414 [MH⁺].

Example 46 N,N-dimethyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionamide(221)

Through similar procedure to the method disclosed in Example 36, whitesolid type of N,N-dimethyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionamide(221; 122 mg) showing following physicochemical property was obtained(yield: 97%).

m.p: 149.3° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.51 (d, 1H,J=1.8 Hz, H-4), 7.41 (d, 1H, J=8.2 Hz, H-5′), 7.17 (dd, 1H, J=1.8, 8.2Hz, H-6), 7.03 (d, 1H, J=8.2 Hz, H-7), 4.01 (s, 3H, OCH₃), 3.11 (t, 2H,J=7.9 Hz, >NCOCH₂), 2.97 (s, 3H, (CH₃)₂N), 2.95 (s, 3H, (CH₃)₂N), 2.69(t, 2H, J=7.9 Hz, CH₂Ar), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 2924, 1627, 1506, 1466, 1279 cm⁻¹;

MS (FAB) m/z 386 [MH⁺], 408 [MNa⁺].

Example 47 N-methyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionamide(22m)

Through similar procedure to the method disclosed in Example 37, whitesolid type of N-methyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionamide(22m; 98 mg) showing following physicochemical property was obtained(yield: 62%).

m.p: 145.4° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.50 (d, 1H,J=1.8 Hz, H-4), 7.40 (d, 1H, J=8.4 Hz, H-5′), 7.14 (dd, 1H, J=1.8, 8.3Hz, H-6), 7.02 (d, 1H, J=8.3 Hz, H-7), 5.83 (s, 1H, OH), 5.33 (bs, 1H,NH), 4.01 (s, 3H, OCH₃), 3.10 (t, 2H, J=7.8 Hz, HNCOCH₂), 2.78 (d, 3H,J=5 Hz, CH₃NH), 2.54 (t, 2H, J=7.8 Hz, CH₂Ar), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3301, 2925, 1644, 1507, 1466, 1279, 1127, 1082, 1030cm⁻¹;

MS (FAB) m/z 372 [MH⁺], 394 [MNa⁺].

Example 483-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-morpholino-1-propanone(22n)

Through similar procedure to the method disclosed in Example 38, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-morpholino-1-propanone(22n; 95 mg) showing following physicochemical property was obtained(yield: 51%).

m.p.: 130.6° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.50 (d, 1H,J=1.7 Hz, H-4), 7.41 (d, 1H, J=8.4 Hz, H-5′), 7.16 (dd, 1H, J=1.7, 8.1Hz, H-6), 7.03 (d, 1H, J=8.1 Hz, H-7), 4.01 (s, 3H, OCH₃), 3.65 (s, 4H,CH₂OCH₂), 3.52 (t, 2H, J=4.7 Hz, CH₂NCH₂), 3.38 (t, 2H, J=4.7 Hz,CH₂NCH₂), 3.12 (t, 2H, J=7.8 Hz, >NCOCH₂), 2.70 (t, 2H, J=7.8 Hz,CH₂Ar), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3434, 1615, 1502, 1465, 1290, 1233, 1113, 1032 cm⁻¹;

MS (EI) m/z 427 [M⁺].

Example 493-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-piperazino-1-propanone(22o)

Through similar procedure to the method disclosed in Example 39, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-piperazino-1-propanone(22o; 124 mg) showing following physicochemical property was obtained(yield: 71%).

m.p: 152.6° C.;

¹H NMR (CDCl₃): δ ppm 7.84-7.9 (m, 2H, H-2′ and H-6′), 7.51 (d, 1H,J=1.6 Hz, H-4), 7.40 (d, 1H, J=8.4 Hz, H-5′), 7.16 (dd, 1H, J=1.6, 8.4Hz, H-6), 7.01 (d, 1H, J=8.4 Hz, H-7), 4.00 (s, 3H, OCH₃), 3.63 (t, 2H,J=5 Hz, CH₂N(C═O)CH₂), 3.39 (t, 2H, J=5 Hz, CH₂N(C═O)CH₂), 2.84 (t, 2H,J=5.3 Hz, CH₂NHCH₂), 2.74 (t, 2H, J=5.3 Hz, CH₂NHCH₂), 3.11 (t, 2H,J=7.9 Hz, >NCOCH₂), 2.70 (t, 2H, J=7.9 Hz, CH₂Ar), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3438, 2920, 1637, 1503, 1465, 1280, 1125, 1027 cm⁻¹;

MS (EI) m/z 426 [M⁺].

Example 503-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperazino)-1-propanone(22p)

Through similar procedure to the method disclosed in Example 40,colorless oil type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperazino)-1-propanone(22p; 136 mg) showing following physicochemical property was obtained(yield: 71%).

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.50 (d, 1H,J=1.8 Hz, H-4), 7.40 (d, 1H, J=8.4 Hz, H-5′), 7.24-7.3 (m, 5H, Ph), 7.16(dd, 1H, J=1.8, 8.4 Hz, H-6), 7.03 (d, 1H, J=8.4 Hz, H-7), 4.01 (s, 3H,OCH₃), 3.65 (t, 2H, J=4.8 Hz, CH₂N(C═O)CH₂), 3.45 (s, 2H, PhCH₂N), 3.39(t, 2H, J=4.8 Hz, CH₂N(C═O)CH₂), 3.10 (t, 2H, J=7.8 Hz, >NCOCH₂), 2.68(t, 2H, J=7.8 Hz, CH₂Ar), 2.38 (t, 2H, J=5.1 Hz, CH₂NCH₂), 2.36 (s, 3H,SCH₃), 2.25 (t, 2H, J=5.1 Hz, CH₂NCH₂);

IR (KBr): δ ppm 2921, 1627, 1504, 1466, 1280, 1030 cm⁻¹;

MS (EI) m/z 516 [M⁺].

Example 513-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperidino)-1-propanone(22q)

Through similar procedure to the method disclosed in Example 41, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-1-(4-benzylpiperidino)-1-propanone(22q; 84 mg) showing following physicochemical property was obtained(yield: 47%).

m.p: 156.6° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.50 (bs, 1H,H-4), 7.41 (d, 1H, J=8.4 Hz, H-5′), 7.0-7.3 (m, 7H, Ph, H-6 and H-7),5.86 (bs, 1H, OH), 4.65 (bd, 1H, J=12.8 Hz, CH₂NCH₂), 4.00 (s, 3H,OCH₃), 3.76 (bd, 1H, J=12.8 Hz, CH₂NCH₂), 3.10 (t, 2H, J=7.8 Hz,>NCOCH₂), 2.84 (bt, 1H, CH₂NCH₂), 2.67 (t, 2H, J=7.8 Hz, CH₂Ar),2.38-2.54 (m, 3H, CH₂NCH₂ and PhCH₂), 2.36 (s, 3H, SCH₃), 1.5-1.75 (m,4H, CH₂CH₂NCH₂CH₂), 0.75-1.2 (m, 1H, BnCH);

IR (KBr): δ ppm 2922, 1616, 1504, 1466, 1280 cm⁻¹;

MS (FAB) m/z 516 [MH⁺].

Example 52(R)-2-(2-(2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)acetamide-4-methylpentylamide(22r)

Through similar procedure to the method disclosed in Example 42, whitesolid type of(R)-2-(2-(2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)acetamide-4-methylpentylamide(22r; 67 mg) showing following physicochemical property was obtained(yield: 95%).

m.p: 179.0° C.;

¹H NMR (CDCl₃): δ ppm 7.84-7.9 (m, 2H, H-2′ and H-6′), 7.49 (d, 1H,J=1.5 Hz, H-4), 7.39 (d, 1H, J=8.4 Hz, H-5′), 7.13 (dd, 1H, J=1.5, 8.4Hz, H-6), 7.02 (d, 1H, J=8.4 Hz, H-7), 6.12 (bs, 1H, NH), 5.87 (bs, 1H,OH), 5.86 (bs, 1H, NH), 5.34 (bs, 1H, NH), 4.45 (m, 1H, CHNH), 34.01 (s,3H, OCH₃), 3.10 (t, 2H, J=7.5 Hz, HNCOCH₂), 2.60 (t, 2H, J=7.5 Hz,CH₂Ar), 2.36 (s, 3H, SCH₃), 1.35-1.65 (m, 3H, CHMe₂ and CH₂CONH₂), 0.86(dd, 6H, J=2.2, 6.2 Hz, CH(CH₃)₂);

IR (KBr): δ ppm 3300, 2957, 1653, 1507, 1465, 1257, 1031 cm⁻¹;

MS (FAB) m/z 471 [MH⁺], 493 [MNa⁺].

Example 53N-phenyl-3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionamide(22s)

Through similar procedure to the method disclosed in Example 43, whitesolid type ofN-phenyl-3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionamide(22s; 85 mg) showing following physicochemical property was obtained(yield: 48%).

m.p: 180.4° C.;

¹H NMR (CDCl₃): δ ppm 7.84-7.9 (m, 2H, H-2′ and H-6′), 7.54 (bs, 1H,H-4), 7.4-7.46 (m, 3H, H-5′ and Ph), 7.25-7.32 (m, 2H, Ph), 7.19 (dd,1H, J=1.5, 8.4 Hz, H-6), 7.09 (m, 1H, Ph), 7.02 (d, 1H, J=8.4 Hz, H-7),6.99 (bs, 1H, NH), 5.82 (s, 1H, OH), 4.01 (s, 3H, OCH₃), 3.20 (t, 2H,J=7.5 Hz, HNCOCH₂), 2.73 (t, 2H, J=7.5 Hz, CH₂Ar), 2.32 (s, 3H, SCH₃);

IR (KBr): δ ppm 3303, 1660, 1599, 1504, 1442, 1254, 1030 cm⁻¹;

MS (FAB) m/z 434 [MH⁺].

Example 54N-benzyl-3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionamide(22t)

Through similar procedure to the method disclosed in Example 44, whitesolid type ofN-benzyl-3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionamide(22t; 113 mg) showing following physicochemical property was obtained(yield: 60%).

m.p: 147.6° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.51 (d, 1H,J=1.5 Hz, H-4), 7.39 (d, 1H, J=8.3 Hz, H-5′), 7.1-7.3 (m, 6H, Ph andH-6), 7.03 (d, 1H, J=8.3 Hz, H-7), 5.84 (s, 1H, OH), 5.60 (bt, 1H, NH),4.41 (d, 2H, J=5.7 Hz, PhCH₂NH), 4.01 (s, 3H, OCH₃), 3.14 (t, 2H, J=7.5Hz, HNCOCH₂), 2.60 (t, 2H, J=7.5 Hz, CH₂Ar), 2.33 (s, 3H, SCH₃);

IR (KBr): δ ppm 3435, 1636, 1543, 1505, 1456, 1255 cm⁻¹;

MS (FAB) m/z 448 [MH⁺]

Example 552-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(23a)

2M ammonia dissolved in 0.5 ml of methanol was added to the solutioncontaining 192.6 mg of pentafluorophenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetate(20a; 0.38 mM) dissolved in 2 ml of methanol cooled at −780. Thereaction mixture was left alone at room temperature, stirred for 5minutes and the solvent was removed. The remaining residue was purifiedwith Silica gel column chromatography with a mobile phase(dichloromethane:methanol=8:1) to obtain white solid type of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide(23a; 130 mg).

Yield: 98%;

m.p: 208° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.91 (m, 2H, H-2′ and H-6′), 7.58 (d, 1H,J=1.7 Hz, H-4), 7.49 (d, 1H, J=8.4 Hz, H-5′), 7.22 (dd, 1H, J=1.7, 8.4Hz, H-6), 7.04 (d, 1H, J=8.4 Hz, H-7), 5.85 (s, 1H, OH), 5.37 (bs, 2H,CONH₂), 4.01 (s, 3H, OCH₃), 3.74 (s, 2H, CH₂Ar), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3753, 3432, 1650, 1507, 1470, 1276, 1209 cm⁻¹;

MS (FAB) m/z 343 [MH⁺].

Example 563-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionamide(23b)

Through similar procedure to the method disclosed in Example 55, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionamide(23b; 141 mg) showing following physicochemical property was obtained(yield: 95%).

m.p: 172.9° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.51 (d, 1H,J=1.8 Hz; H-4), 7.41 (d, 1H, J=8.4 Hz, H-5′), 7.18 (dd, 1H, J=1.8, 8.1Hz, H-6), 7.02 (d, 1H, J=8.1 Hz, H-7), 5.83 (s, 1H, OH), 5.38 (bs, 2H,CONH₂), 4.01 (s, 3H, OCH₃), 3.11 (t, 2H, J=7.6 Hz, H₂NCOCH₂), 2.62 (t,2H, J=7.6 Hz, CH₂Ar), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3346, 1659, 1604, 1506, 1466, 1278, 1127, 1030 cm⁻¹;

MS (FAB) m/z 358 [MH⁺].

Example 572-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)ethylamine(24a)

Through similar procedure to the method disclosed in Example 13, whitesolid type of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-ylethylamine(24a; 85 mg) showing following physicochemical property was obtained(yield: 62%).

m.p: 180.9° C.;

¹H NMR (CD₃OD): δ ppm 7.96 (d, 1H, J=2 Hz, H-2′), 7.79 (dd, 1H, J=2, 8.4Hz, H-6′), 7.59 (d, 1H, J=1.8 Hz, H-4), 7.50 (d, 1H, J=8.4 Hz, H-5′),7.23 (dd, 1H, J=1.8, 8.4 Hz, H-6), 6.91 (d, 1H, J=8.1 Hz, H-7), 3.95 (s,3H, OCH₃), 3.23 (t, 2H, J=7.8 Hz, H₂NCH₂), 3.08 (t, 2H, J=7.8 Hz,CH₂Ar), 2.37 (s, 3H, SCH₃);

IR (KBr): δ ppm 3435, 1605, 1500, 1468, 1291, 1233, 1126, 1084, 1030cm⁻¹;

MS (FAB) m/z 330 [MH⁺].

Example 583-[2-(4″-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propylamine(24b)

Through similar procedure to the method disclosed in Example 13, whitesolid type of3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propylamine(24b; 96 mg) showing following physicochemical property was obtained(yield: 65%).

m.p: 163.1° C.;

¹H NMR (CD₃OD): δ ppm 7.95 (d, 1H, J=2 Hz, H-2′), 7.78 (dd, 1H, J=2, 8.4Hz, H-6′), 7.52 (d, 1H, J=1.8 Hz, H-4), 7.44 (d, 1H, J=8.4 Hz, H-5′,7.19 (dd, 1H, J=1.8, 8.2 Hz, H-6), 6.91 (d, 1H, J=8.2 Hz, H-7), 3.95 (s,3H, OCH₃), 2.93 (t, 2H, J=7.6 Hz, H₂NCH₂), 2.85 (t, 2H, J=7.6 Hz,CH₂Ar), 2.36 (s, 3H, SCH₃), 2.01 (dt, 2H, H₂NCH₂CH₂);

IR (KBr): δ ppm 3395, 1555, 1464, 1279, 1128 cm⁻¹;

MS (FAB) m/z 343 [M⁺].

Example 59 BenzylN-2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]ethylcarbomate(25a)

0.04 ml of benzylchloroform (0.28 mM) was added to the solutioncontaining 91.3 mg of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)ethylamine(24a; 0.28 mM) dissolved in 2 ml of THF. The reaction mixture was heatedat 65□ and stirred for 2 hours. The reacted product was extracted withethylacetate, dried with magnesium sulfate and the solvent was removed.The remaining residue was purified with Silica gel column chromatographywith a mobile phase (hexane:ethylacetate=4:1) to obtain colorless oiltype of benzylN-2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]ethylcarbomate(25a; 130 mg).

Yield: 95%;

¹H NMR (CDCl₃): δ ppm 7.85-7.9 (m, 2H, H-2′ and H-6′), 7.49 (bs, 1H,H-4), 7.41 (d, 1H, J=8.3 Hz, H-5′), 7.3-7.37 (m, 5H, Ph), 7.12 (bd, 1H,8.4 Hz, H-6), 7.03 (d, 1H, J=8.4 Hz, H-7), 5.84 (s, 1H, OH), 5.10 (s,2H, PhCH₂O), 4.79 (bs, 1H, NH), 4.01 (s, 3H, OCH₃), 3.53 (dd, 2H,CONHCH₂), 2.95 (t, 2H, J=7 Hz, CH₂Ar), 2.34 (s, 3H, SCH₃);

IR (KBr): δ ppm 2927, 1765, 1605, 1502, 1466, 1243, 1207, 1175, 1035cm⁻¹;

MS (FAB) m/z 486 [MNa⁺].

Example 60 BenzylN-3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propylcarbomate(25b)

Through similar procedure to the method disclosed in Example 59,colorless oil type of benzylN-3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propylcarbomate(25b; 143 mg) showing following physicochemical property was obtained(yield: 98%).

¹H NMR (CDCl₃): δ ppm d 8.01 (d, 1H, J=1.8 Hz, H-2′), 7.92 (dd, 1H,J=1.8, 8.4 Hz, H-6′), 7.53 (d, 1H, J=2 Hz, H-4), 7.35-7.48 (m, 6H, H-5′and Ph), 7.24 (d, 1H, J=8.4 Hz, H-7), 7.19 (dd, 1H; J=2, 8.4 Hz, H-6),5.31 (s, 2H, PhCH₂O), 3.93 (s, 3H, OCH₃), 3.73 (t, 2H, CONHCH₂), 2.86(t, 2H, J=7.6 Hz, CH₂Ar), 2.38 (s, 3H, SCH₃), 1.97 (dt, 2H, CONHCH₂CH₂);

IR (KBr): δ ppm 2928, 1765, 1605, 1502, 1465, 1243, 1207, 1175, 1035cm⁻¹;

MS (FAB) m/z 501.0 [MNa⁺].

Example 61 Methyl3-[2-(4′-(3-chloropropoxy)-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionate (26)

991.2 mg of 1-bromo-3-chloropropane (6.3 mM) was added to the solutioncontaining 343 mg of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetate(9a; 0.28 mM) and 522.43 mg of potassium carbonate (3.78 mM) dissolvedin 7 ml of acetone. The reaction mixture was heated for 2-3 days at60-65° C. and remaining potassium carbonate and solvent were removed.The remaining residue was purified with Silica gel column chromatographywith a mobile phase (hexane:ethylacetate=4:1) to obtain white solid typeof methyl3-[2-(4′-(3-chloropropoxy)-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionate (26; 565 mg).

Yield: 85%;

m.p: 85.5° C.;

¹H NMR (CDCl₃): δ ppm d 7.92 (d, 1H, J=2 Hz, H-2′), 7.88 (dd, 1H, J=2,8.3 Hz, H-6′), 7.51 (d, 1H, J=1.5 Hz, H-4), 7.41 (d, 1H, J=8.3 Hz,H-5′), 7.15 (dd, 1H, J=1.5, 8.4 Hz, H-6); 7.01 (d, 1H, J=8.4 Hz, H-7),4.25 (t, 2H, J=6.0 Hz, ArOCH₂), 3.97 (s, 3H, OCH₃), 3.80 (t, 2H, J=6.3Hz, CH₂Cl), 3.69 (s, 3H, CO₂CH₃), 3.09 (t, 2H, J=7.8 Hz, MeO₂CCH₂), 2.71(t, 2H, J=7.8 Hz, CH₂Ar), 2.37 (s, 3H, SCH₃), 2.33 (m, 2H, ArOCH₂CH₂).

Example 62 Methyl3-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionate (27)

0.1 ml of diethylamine (1.05 mM) was added to the solution containing315.9 mg of3-[2-(4′-(3-chloropropoxy)-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionate (26; 0.7 mM) dissolved in 7 ml of methanol. The reactionmixture was heated for 2-3 days at 70° C. and remaining solvent wereremoved. The remaining residue was purified with Silica gel columnchromatography with a mobile phase (hexane:ethylacetate=4:1) to obtainwhite solid type of methyl3-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl)propionate (27; 341 mg).

Yield: 92%;

m.p: 66.1° C.;

¹H NMR (CDCl₃): δ ppm d 7.91 (d, 1H, J=2 Hz, H-2′), 7.87 (dd, 1H, J=2,8.3 Hz, H-6′), 7.50 (d, 1H, J=1.8 Hz, H-4), 7.41 (d, 1H, J=8.3 Hz,H-5′), 7.14 (dd, 1H, J=1.8, 8.6 Hz, H-6), 7.00 (d, 1H, J=8.6 Hz, H-7),4.15 (t, 2H, J=6.7 Hz, ArOCH₂), 3.97 (s, 3H, OCH₃), 3.69 (s, 3H,CO₂CH₃), 3.09 (t, 2H, J=7.8 Hz, MeO₂CCH₂), 2.71 (t, 2H, J=7.8 Hz,CH₂Ar), 2.64 (t, 2H, J=7.1 Hz, CH₂NEt₂), 2.55 (q, 4H, J=7.1 Hz,2×NCH₂CH₃), 2.37 (s, 3H, SCH₃), 2.02 (m, 2H, ArOCH₂CH₂), 1.04 (t, 6H,J=7.1 Hz, 2×NCH₂CH₃);

IR (KBr): δ ppm 2965, 1738, 1506, 1466, 1251, 1144, 1032 cm⁻¹;

MS (FAB) m/z 486 [MH⁺].

Example 63 Methyl3-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxyphenyl)-benzofuran-5-yl)propionate(28)

Through similar procedure to the method disclosed in Example 3, whitesolid type of N-methyl3-[2-(4′13-(diethylamino)propoxy]-3′-methoxyphenyl)-benzofuran-5-yl)propionate(28; 350 mg) showing following physicochemical property was obtained(yield: 84%).

m.p: 168.8° C.;

¹H NMR (CDCl₃): δ ppm d 7.36-7.44 (m, 4H, Ar), 7.10 (dd, 1H, J=1.8, 8.3Hz, H-6), 6.94 (d, 1H, J=8.3 Hz, H-7), 6.87 (s, 1H, H-3), 4.18 (t, 2H,J=5.5 Hz, ArOCH₂), 3.95 (s, 3H, OCH₃), 3.68 (s, 3H, CO₂CH₃), 3.27 (t,2H, J=7.8 Hz, CH₂NEt₂), 3.15 (q, 4H, J=7.3 Hz, 2×NCH₂CH₃), 3.04 (t, 2H,J=7.7 Hz, MeO₂CCH₂), 2.68 (t, 2H, J=7.7 Hz, CH₂Ar), 2.42 (m, 2H,ArOCH₂CH₂), 1.44 (t, 6H, J=7.3 Hz, 2×NCH₂CH₃);

IR (KBr): δ ppm 3741, 3395, 2952, 1734, 1513, 1460, 1227, 1142, 1026cm⁻¹;

MS (FAB) m/z 440 [MH⁺].

Example 643-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxyphenyl}-3-(methylthio)-benzofuran-5-yl)propanol(29)

Through similar procedure to the method disclosed in Example 13, whitesolid type of3-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxyphenyl}-3-(methylthio)-benzofuran-5-yl)propanol(29; 270 mg) showing following physicochemical property was obtained(yield: 62%).

m.p: 114.2° C.;

¹H NMR (CDCl₃): δ ppm d 7.91 (d, 1H, J=1.8 Hz, H-2′), 7.88 (dd, 1H,J=1.8, 8.4 Hz, H-6′), 7.50 (d, 1H, J=1.5 Hz, H-4), 7.41 (d, 1H, J=8.4Hz, H-5′), 7.16 (dd, 1H, J=1.5, 8.4 Hz, H-6), 6.97 (d, 1H, J=8.4 Hz,H-7), 4.20 (t, 2H, J=5 Hz, ArOCH₂), 3.95 (s, 3H, OCH₃), 3.72 (t, 2H,J=6.3 Hz, HOCH₂), 3.29 (t, 2H, J=7.8 Hz, CH₂NEt₂), 3.17 (q, 4H, J=7.2Hz, 2×NCH₂CH₃), 2.85 (t, 2H, J=7.7 Hz, CH₂Ar), 2.42 (m, 2H, ArOCH₂CH₂),2.38 (s, 3H, SCH₃), 1.97 (m, 2H, HOCH₂CH₂), 1.45 (t, 6H, J=7.2 Hz,2×NCH₂CH₃);

IR (KBr): δ ppm 3393, 2941, 1648, 1506, 1467, 1249, 1143, 1034 cm⁻¹;

MS (FAB) m/z 458 [MH⁺].

Example 653-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxyphenyl}-3-benzofuran-5-yl)propanol(30)

Through similar procedure to the method disclosed in Example 13, whitesolid type of3-[2-{4′-[3-(diethylamino)propoxy]-3′-methoxyphenyl}-3-benzofuran-5-yl)propanol(30; 220 mg) showing following physicochemical property was obtained(yield: 58%).

m.p: 149.8° C.;

¹H NMR (CDCl₃): δ ppm d 7.36-7.44 (m, 4H, Ar), 7.10 (dd, 1H, J=1.8, 8.3Hz, H-6), 6.94 (d, 1H, J=8.3 Hz, H-7), 6.87 (s, 1H, H-3), 4.18 (t, 2H,J=5 Hz, ArOCH₂), 3.95 (s, 3H, OCH₃), 3.71 (t, 2H, J=6.4 Hz, HOCH₂), 3.28(t, 2H, J=7.7 Hz, CH₂NEt₂), 3.17 (q, 4H, J=7.3 Hz, 2×NCH₂CH₃), 2.81 (t,2H, J=7.7 Hz, CH₂Ar), 2.43 (m, 2H, ArOCH₂CH₂), 1.95 (m, 2H, HOCH₂CH₂),1.45 (t, 6H, J=7.3 Hz, 2×NCH₂CH₃);

IR (KBr): δ ppm 3366, 2947, 2618, 1511, 1471, 1253, 1140, 1059 cm⁻¹; MS(FAB) m/z 412 [MH⁺].

Example 66[2-(3,4-dimethoxy-phenyl)-3-(methylsulfanyl)-benzofuran-5-yl)acetic acidmethyl ester (31a)

174 mg of potassium carbonate (1.26 mM) and 298 mg of iodomethane (2.1mM) were added to the solution containing 145 ml of2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-1-benzofuran-5-yl]acetate(7a; 0.42 mM) dissolved in 1 ml of acetone. The reaction mixture wasrefluxed for 3 hours and remaining inorganic substances were removedwith filtration. The remaining solvent was removed. The remainingresidue was purified with Silica gel column chromatography with a mobilephase (hexane:ethylacetate=4:1) to obtain white solid type of[2-(3,4-dimethoxy-phenyl)-3-(methylsulfanyl)-benzofuran-5-yl)acetic acidmethyl ester (31a; 100 mg).

Yield: 64%;

m.p: 91° C.;

¹H NMR (CDCl₃): δ ppm d 7.92 (s, 1H), 7.88 (d, 1H, J=2.0 z), 7.58 (d,1H, J=1.7 z,), 7.44 (d, 1H, J=8.3 Hz), 7.22 (dd, 1, J=8.4 & 1.7 Hz, 6.96(d, 1H, J=8.3), 3.99 (s, 3), 3.93 (s, 3H), 3.75 (s, 2H), 3.71 (s, 3H),3.37 (s, 3H);

IR (KBr): δ ppm 2922, 1737, 1605, 1507, 1467, 1253, 1144, 1024, 808cm⁻¹;

MS (FAB+) m/z 372 [M⁺].

Example 673-[2-(3,4-dimethoxyphenyl)-3-methylsulfanyl-benzofuran-5-yl]propionicacid methyl ester (31b)

Through similar procedure to the method disclosed in Example 66, whitesolid type of3-[2-(3,4-dimethoxyphenyl)-3-methylsulfanyl-benzofuran-5-yl]propionicacid methyl ester (31b; 130 mg) showing following physicochemicalproperty was obtained (yield: 98.9%).

m.p: 85˜87° C.;

¹H NMR (CDCl₃): δ ppm d 7.92-7.88 (m, 2H), 7.51 (d, 1H, J=1.3 Hz), 7.42(d, 1H, J=8.4 Hz), 7.15 (dd, 1H, J=8.3, 1.8 Hz), 6.99 (d, 1H, J=7.0 Hz),4.00 (s, 3H), 3.96 (s, 3H), 3.69 (s, 3H), 3.09 (t, 2H, J=7.5 Hz), 2.71(t, 2H, J=8.0 Hz), 2.38 (s, 3H);

IR (KBr): δ ppm 2924, 1737, 1507, 1467, 1254, 1146, 1027 cm⁻¹;

MS (FAB+) m/z 386 [M⁻¹].

Example 68 [2-(3,4-dimethoxyphenyl)-benzofuran-5-yl]acetic acid methylester (32a)

Through similar procedure to the method disclosed in Example 66, whitesolid type of [2-(3,4-dimethoxyphenyl)-benzofuran-5-yl]acetic acidmethyl ester (32a; 136 mg) showing following physicochemical propertywas obtained (yield: 95.8%).

m.p: 119° C.;

¹H NMR (CDCl₃): δ ppm d 7.45-7.34 (m, 4H), 7.15 (d, 1H, J=8.43 Hz), 6.90(dd, 1H, J=8.43 Hz & J=1.83 Hz), 6.84 (d, 1H, J=1.29), 3.96 (s, 3H),3.90 (s, 3H), 3.7-3.66 (m, 5H);

IR (KBr): δ ppm 2927, 1736, 1609, 1511, 1466, 1255, 1144, 1024, 939,860, 802 cm⁻¹;

MS (FAB+) m/z 326 [M⁺].

Example 69 3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propionic acidmethyl ester (32b)

Through similar procedure to the method disclosed in Example 66, whitesolid type of 3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propionicacid methyl ester (32b; 155 mg) showing following physicochemicalproperty was obtained (yield: 98.8%).

m.p: 105˜107° C.;

¹H NMR (CDCl₃): δ ppm d 7.45-7.36 (m, 4H), 7.09 (dd, 1H), 6.94 (d, 1H,J=8.4 Hz), 6.86 (d, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.68 (s, 3H), 3.05(t, 2H), 2.68 (t, 2H);

IR (KBr): δ ppm 2927, 1737, 1511, 1468, 1254, 1170, 1144, 1026 cm⁻¹;

MS (FAB+) m/z 340 [M⁺].

Example 70[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-acetic acid(33a)

Through similar procedure to the method disclosed in Example 5, whitesolid type of3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-aceticacid (33a; 260 mg) showing following physicochemical property wasobtained (yield: 94.3%).

m.p: 165° C.;

¹H NMR (CDCl₃): δ ppm d 7.91 (s, 1H), 7.88 (d, 1H, J=2.0 Hz), 7.58 (d,1H, J=1.29 Hz), 7.45 (d, 1H, J=8.4 Hz), 7.23 (dd, 1H, J=8.43 Hz & J=1.65Hz), 6.97 (d, 1H, J=8.25), 4.0 (s, 3H), 3.95 (s, 3H), 3.78 (s, 2H), 2.36(s, 3H);

IR (KBr): δ ppm 2920, 1706, 1506, 1466, 1253, 1145, 1090, 1026, 965,802, 760 cm⁻¹;

MS (FAB+) m/z 358 [M⁺].

Example 713-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propionicacid (33b)

Through similar procedure to the method disclosed in Example 5, whitesolid type of3-3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propionicacid (33b; 320 mg) showing following physicochemical property wasobtained (yield: 97.6%).

m.p: 164˜166° C.;

¹H NMR (CD₃OD): δ ppm d 7.97 (d, 1H, J=2.0 Hz), 7.87 (dd, 1H, J=8.6, 2.2Hz), 7.53 (d, 1H, J=1.1 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.20 (dd, 1H,J=8.4, 1.8 Hz), 7.07 (d, 1H, J=8.6 Hz), 3.92 (s, 3H), 3.89 (s, 3H), 3.04(t, 2H, J=7.5 Hz), 2.66 (t, 2H, J=7.5 Hz), 2.36 (s, 3H);

IR (KBr): δ ppm 2921, 1706, 1502, 1445, 1246, 1145, 1090, 1026 cm⁻¹;

MS (FAB+) m/z 372 [M⁺].

Example 72 [2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-acetic acid (34a)

Through similar procedure to the method disclosed in Example 5, whitesolid type of [2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-acetic acid(34a; 554 mg) showing following physicochemical property was obtained(yield: 96.1%).

m.p: 202° C.;

¹H NMR (CD₃OD): δ ppm d 7.46 (m, 4H), 7.20 (m, 1H), 7.03 (m, 2H), 3.93(s, 3H), 3.88 (s, 3H), 3.65 (s, 3H);

IR (KBr): δ ppm 2482, 1727, 1602, 1503, 1462, 1250, 1134, 1014, 931, 853cm⁻¹;

MS (FAB+) m/z 312 [M⁺].

Example 73 3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propionic acid(34b)

Through similar procedure to the method disclosed in Example 5, whitesolid type of 3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propionicacid (34b; 554 mg) showing following physicochemical property wasobtained (yield: 95.8%).

m.p: 105˜107° C.;

¹H NMR (CD3OD): δ ppm d 7.47-7.37 (m, 4H), 7.12 (dd, 1H, J=8.4, 1.8 Hz),7.02 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=0.8 Hz), 3.91 (s, 3H), 3.87 (s,3H), 2.99 (t, 2H, J=7.7 Hz), 2.63 (t, 2H, J=7.7 Hz);

MS (FAB+) m/z 340[M⁺].

Example 74[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-acetic acid(35a)

Through similar procedure to the method disclosed in Example 5, whitesolid type of3[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-acetic acid(35a; 720 mg) showing following physicochemical property was obtained(yield: 80%).

m.p: 90˜92° C.;

¹H NMR (CDCl₃): δ ppm 7.54 (s, 1H), 7.51 (d, 1H, J=8.4 Hz), 7.46 (dd,1H, J=8.43 Hz &, J=2.01), 7.37 (d, 1H, J=2.04 Hz), 7.23 (dd, 1H, J=8.43Hz & J=2.01 Hz), 6.95 (d, 1H, J=8.4), 6.90 (s, 1H) 4.06 (s, 2H), 4.0 (s,3H), 3.95 (s, 3H);

IR (KBr): δ ppm 2928, 2856, 1790, 1718, 1518, 1466, 1254, 1141, 1088,999, 801 cm⁻¹.

Example 753-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propionicacid pentafluorophenyl ester (35b)

Through similar procedure to the method disclosed in Example 5, whitesolid type of3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propionicacid pentafluorophenyl ester (35b; 710 mg) showing followingphysicochemical property was obtained (yield: 79%).

m.p: 111˜113° C.;

¹H NMR (CDCl₃): δ ppm d 7.98-7.90 (m, 2H), 7.57 (d, 1H, J=1.6 Hz), 7.45(d, 1H, J=8.3 Hz), 7.20 (dd, 1H, J=8.4, 1.8 Hz), 6.99 (d, 1H, J=8.3 Hz),4.01 (s, 3H), 3.96 (s, 3H), 3.23 (t, 2H, J=7.5 Hz), 3.07 (t, 2H, J=7.7Hz), 2.38 (s, 3H);

IR (KBr): δ ppm 2926, 1789, 1520, 1469, 1254, 1145, 1096, 999 cm⁻¹.

Example 76 [2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-acetic acidpentafluorophenyl ester (36a)

Through similar procedure to the method disclosed in Example 5, whitesolid type of 3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-acetic acidpentafluorophenyl ester (36a; 540 mg) showing following physicochemicalproperty was obtained (yield: 69.4%).

m.p: 127° C.;

¹H NMR (CDCl₃): 5 ppm d 7.54 (s, 1H), 7.51 (d, 1H, J=8.4 Hz), 7.46 (dd,1H, J=8.43 Hz &, J=2.01), 7.37 (d, 1H, J=2.04 Hz), 7.23 (dd, 1H, J=8.43Hz & J=2.01 Hz), 6.95 (d, 1H, J=8.4), 6.90 (s, 1H) 4.06 (s, 2H), 4.0 (s,3H), 3.95 (s, 3H);

IR (KBr): 5 ppm 2928, 2856, 1790, 1718, 1518, 1466, 1254, 1141, 1088,999, 801 cm⁻¹;

MS (FAB+) m/z 388 [M⁺].

Example 77 3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propionic acidpentafluorophenyl ester (36b)

Through similar procedure to the method disclosed in Example 5, whitesolid type of 3-3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propionicacid pentafluorophenyl ester (36b; 563 mg) showing followingphysicochemical property was obtained (yield: 99%).

m.p: 98˜100° C.;

¹H NMR (CDCl₃): δ ppm d 7.47-7.37 (m, 4H), 7.14 (dd, 1H, J=8.4, 1.8 Hz),6.95 (d, 1H, J=8.4 Hz), 6.87 (d, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.18(t, 2H, J=7.7 Hz), 3.04 (t, 2H, J=7.1 Hz);

IR (KBr): 5 ppm 2926, 1787, 1520, 1469, 1254, 1143, 1098, 998 cm⁻¹;

MS (FAB+) m/z 326 [M⁺].

Example 782-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone(37a)

Triethylamine and 12.992 mg of 1-phenyl-piperazine (0.080 mM) were addedto the solution containing 35 mg of3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-aceticacid (35a; 0.068 mM) dissolved in 2 ml of dichloromethane. The reactionmixture was stirred for 16 hours and the remaining solvent was removed.The remaining residue was purified with Silica gel column chromatographywith a mobile phase (dichloromethane:methanol=20:1) to obtain whitesolid type of2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone(37a; 223 mg).

Yield: 95.7%;

m.p: 160° C.;

¹H NMR (CDCl₃): 5 ppm d 7.91 (S, 1H), d 7.88 (d, 1H, J=2.01) d 7.55 (d,1H, J=1.29), 7.44 (d, 1H, J=8.43 Hz), 7.28-7.17 (m, 3H), 6.96 (d, 1H,J=8.79), 6.89 (m, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 3.93 (s, 2H), 3.85(t, 2H, J=6), 3.67 (t, 2H, J=4.77), 3.16 (t, 2H, J=5.13), 2.98 (t, 2H,J=5.13), 2.34 (s, 3H);

IR (KBr): δ ppm 2921, 1643, 1600, 1509, 1464, 1253, 1230, 1145, 1024,758, 694 cm⁻¹;

MS (FAB+) m/z 503 [MH⁺].

Example 793-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-1-(4-phenyl-piperazin-1yl)-propan-1-one(37b)

Through similar procedure to the method disclosed in Example 5, whitesolid type of3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-1-(4-phenyl-piperazin-1-yl)-propan-1-one(37b; 250 mg) showing following physicochemical property was obtained(yield: 99%).

m.p: 118˜120° C.;

¹H NMR (CDCl₃): δ ppm d 7.91-7.89 (m, 2H), 7.53 (s, 1H), 7.42 (d, 1H,J=8.3 Hz), 7.26-7.17 (m, 3H), 6.98 (d, 1H, J=9.2 Hz), 6.90-6.86 (m, 3H),4.00 (s, 3H), 3.96 (s, 3H), 3.80 (m, 2H), 3.55 (m, 2H), 3.17-3.12 (m,4H), 2.99 (m, 2H), 2.75 (t, 2H, J=8.3 Hz), 2.36 (s, 3H);

IR (KBr): δ ppm 2923, 1644, 1601, 1504, 1466, 1253, 1146, 1023, 758cm⁻¹;

MS (FAB+) m/z 516 [MH⁺].

Example 801-(4-benzyl-piperazin-1-yl)-2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanone(37c)

Through similar procedure to the method disclosed in Example 78, whitesolid type of1-(4-benzyl-piperazin-1-yl)-2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanone(37c; 114 mg) showing following physicochemical property was obtained(yield: 98.2%).

m.p: 70° C.;

¹H NMR (CDCl₃): δ ppm d 7.91 (m, 2H); d 7.50 (d, 1H, J=1.44), 7.42 (d,1H, J=8.43 Hz), 7.3-7.2 (m, 5H), 7.15 (dd, 1H, J=8.4 & J=81.83 Hz), 6.99(d, 1H, J=8.22 Hz), 4.0 (s, 3H), 3.96 (s, 3H), 3.86 (s, 2H), 3.73 (t,2H, J=4.59), 3.55 (m, 4H), 2.52 (t, 2H, J=4.77), 2.35 (m, 5H);

IR (KBr): δ ppm 2922, 1642, 1509, 1465, 1348, 1253, 1144, 989, 754, 699cm⁻¹;

MS (FAB+) m/z 517 [MH⁺].

Example 811-(4-benzyl-piperazin-1-yl)-3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propan-1-one(37d)

Through similar procedure to the method disclosed in Example 78, whitesolid type of1-(4-benzyl-piperazin-1-yl)-3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propan-1-one(37d; 102 mg) showing following physicochemical property was obtained(yield: 97%).

m.p: 100˜102° C.;

¹H NMR (CDCl₃+CD₃OD): δ ppm d 7.99 (d, 1H, J=1.8 Hz), 7.95 (dd, 1H,J=8.4, 2.0 Hz), 7.51 (d, 1H), 7.45 (d, 1H, J=8.4 Hz), 7.27-7.17 (m, 6H),7.06 (d, 1H, J=8.4 Hz), 3.99 (s, 3H), 3.96 (s, 3H), 3.61 (m, 2H), 3.37(m, 4H), 3.10 (t, 2H, J=7.1 Hz), 2.38 (m, 5H), 2.04 (m, 2H);

IR (KBr): δ ppm 2925, 1642, 1509, 1467, 1347, 1254, 1145, 1000, 753cm⁻¹;

MS (FAB+) m/z 531 [MH⁺].

Example 822-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-1-(4-phenyl-piperazin-1-yl)-ethanone(38a)

Through similar procedure to the method disclosed in Example 78, whitesolid type of2-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-1-(4-phenyl-piperazin-1-yl)-ethanone(38a; 95 mg) showing following physicochemical property was obtained(yield: 92%).

m.p: 54° C.;

¹H NMR (CDCl₃): δ ppm d 7.4-7.2 (m, 9H), 7.07 (d, 1, J=6.96 Hz), 6.4 (d,1H, J=8.43 Hz), 6.82 (s, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.81 (s, 2H),3.73 (s, 2H), 3.55 (s, 4H), 2.54 (s, 2H), 2.33 (s, 2H);

IR (KBr): δ ppm 2936, 1640, 1511, 1465, 1346, 1253, 1142, 989, 862, 801,754, 701 cm⁻¹;

MS (FAB+) m/z 471 [MH⁺].

Example 833-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-1-(4-phenyl-piperazin-1-yl)-propan-1-one(38b)

Through similar procedure to the method disclosed in Example 78, whitesolid type of3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-1-(4-phenyl-piperazin-1-yl)-propan-1-one(38b; 86 mg) showing following physicochemical property was obtained(yield: 98%).

m.p: 122˜124° C.;

¹H NMR (CDCl₃): δ ppm d 7.44-7.35 (m, 4H), 7.26-7.21 (m, 2H), 7.12 (dd,1H), 6.96-6.84 (m, 5H), 3.99 (s, 3H), 3.94 (s, 3H), 3.79 (t, 2H), 3.53(t, 2H), 3.12-3.06 (m, 4H), 2.97 (t, 2H), 2.72 (t, 2H, J=8.3 Hz);

IR (KBr): δ ppm 2924, 1645, 1510, 1464, 1253, 1144, 1023 cm⁻¹;

MS (FAB+) m/z 471 [MH⁺].

Example 841-(4-benzyl-piperazin-1-yl)-2-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-ethanone(38c)

Through similar procedure to the method disclosed in Example 78, whitesolid type of1-(4-benzyl-piperazin-1-yl)-2-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-ethanone(38c; 97 mg) showing following physicochemical property was obtained(yield: 93.4%).

m.p: 129° C.;

¹H NMR (CDCl₃): δ ppm d 7.42 (m, 3H), d 7.24 (m, 2H) 7.15 (m, 1H), 6.94(d, 1H, J=8.61 Hz), 6.88 (s, 2H), 6.86 (s, 2H), 3.99 (s, 3H), 3.94 (s,3H), 3.88 (s, 2H), 3.83 (s, 2H), 3.65 (s, 2H), 3.16 (s, 2H), 2.98 (s,2H);

IR (KBr): δ ppm 2917, 1601, 1512, 1466, 1342, 1252, 1143, 1022, 862,758, 694 cm⁻¹;

MS (FAB+) m/z 457 [MH⁺].

Example 851-(4-benzyl-piperazin-1-yl)-3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propan-1-one(38d)

Through similar procedure to the method disclosed in Example 78, whitesolid type of1-(4-benzyl-piperazin-1-yl)-3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propan-1-one(38d; 96 mg) showing following physicochemical property was obtained(yield: 98%).

m.p: 87˜89° C.;

¹H NMR (CDCl₃): δ ppm d 7.45-7.23 (m, 9H), 7.09 (dd, 1H), 6.95 (d, 1H,J=8.6 Hz), 6.85 (s, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.64 (t, 2H), 3.44(s, 2H), 3.37 (t, 2H), 3.06 (t, 2H, J=7.0 Hz), 2.66 (t, 2H, J=7.9 Hz),2.40 (t, 2H), 2.20 (t, 2H);

IR (KBr): δ ppm 2928, 1643, 1511, 1465, 1254, 1142, 1023 cm⁻¹;

MS (FAB+) m/z 485 [MH⁺].

Example 862-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanol(39a)

Through similar procedure to the method disclosed in Example 13, whitesolid type of2-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanol(39a; 164 mg) showing following physicochemical property was obtained(yield: 90%).

m.p: 96° C.;

¹H NMR (CDCl₃): δ ppm d 7.92 (s, 1H), 7.89 (d, 1H, J=1.83 Hz), 7.53 (d,1H, J=1.65 Hz), 7.44 (d, 1H, J=8.25 Hz), 7.17 (dd, 1H, J=8.43 & 1.65Hz), 6.97 (d, 1H, J=8.04), 4.0 (s, 3H), 3.95 (s, 3H), 3.92 (t, 2H, J=6.6Hz), 3.0 (t, 2H, J=6.42), 2.38 (s, 3H);

IR (KBr): δ ppm 3499, 2925, 1507, 1466, 1253, 1144, 1026, 860, 807, 760cm⁻¹;

MS (FAB+) m/z 344 [M⁺].

Example 873-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propan-1-ol(39b)

Through similar procedure to the method disclosed in Example 13, whitesolid type of3-[2-(3,4-dimethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-propan-1-ol(39b, 184 mg) showing following physicochemical property was obtained(yield: 99%).

m.p: 87˜89° C.;

¹H NMR (CDCl₃): δ ppm d 7.92-7.89 (m, 2H), 7.51 (s, 1H), 7.42 (d, 1H,J=8.4 Hz), 7.16 (d, 1H, J=8.0 Hz), 6.98 (d, 1H, J=8.3 Hz), 4.00 (s, 3H),3.96 (s, 3H), 3.73 (t, 2H, J=6.1 Hz), 2.85 (t, 2H, J=7.3 Hz), 2.38 (s,3H), 1.98 (m, 2H);

IR (KBr): δ ppm 3365, 2926, 1605, 1506, 1467, 1254, 1174, 1145, 1027cm⁻¹;

MS (FAB+) m/z 358 [M⁺].

Example 88 2-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-ethanol (40a)

Through similar procedure to the method disclosed in Example 13, whitesolid type of 2-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-ethanol (40a,225 mg) showing following physicochemical property was obtained (yield:97%).

m.p: 122° C.;

¹H NMR (CDCl₃): δ ppm d 7.47-7.41 (m, 3H), 7.38 (m, 1H), 7.14 (m, 1H),6.95 (d, 1H, J=8.25 Hz), 6.87 (s, 1H), 4.0 (s, 3H), 3.94 (s, 3H), 3.85(t, 2H, J=7.1 Hz), 2.96 (t, 2H, J=6.6 Hz);

IR (KBr): δ ppm 3394, 2933, 1608, 1511, 1466, 1252, 1142, 1025, 941,860, 804, 762 cm⁻¹;

MS (FAB+) m/z 298 [M⁺].

Example 89 3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propan-1-ol(40b)

Through similar procedure to the method disclosed in Example 13, whitesolid type of 3-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-propan-1-ol(40b, 235 mg) showing following physicochemical property was obtained(yield: 76%).

m.p: 99˜101° C.;

¹H NMR (CDCl₃): δ ppm d 7.45-7.36 (m, 4H), 7.10 (dd, 1H), 6.94 (d, 1H,J=8.4 Hz), 6.86 (d, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.71 (m, 2H), 2.81(t, 2H, J=7.5 Hz), 2.00-1.90 (m, 2H);

IR(KBr): δ ppm 3339, 2926, 1513, 1469, 1256, 1228, 1169, 1143, 1023cm⁻¹;

MS (FAB+) m/z 312 [M⁺].

Example 903-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dipropylpropanamide

Through similar procedure to the method disclosed in Example 59,3-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,Ndipropylpropanamide showing following physicochemical property wasobtained.

Yield: 81%;

m.p: 185° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.89 (dd, 1H, J=1.8, 8.4 Hz, H-6′), 7.51 (s,1H), 7.40 (d, 1H, J=8.4 Hz, H-5′), 7.17 (dd, 1H, J=8.2 Hz), 7.02 (d, 1H,J=8.2 Hz), 5.85 (s, 1H), 4.01 (s, 3H, OCH₃), 3.27 (t, 2H, J=8.7 Hz),3.08-3.15 (m, 4H), 2.67 (t, 2H, J=8.7 Hz), 3.08-3.15 (m, 4H), 2.66 (t,2H, J=6.3 Hz), 2.36 (s, 3H), 1.49-1.58 (m, 4H), 0.84-0.90 (m, 6H)

Example 913-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-oneshowing following physicochemical property was obtained

Yield: 71%;

m.p: 147° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.89 (dd, 1H, J=1.8, 8.4 Hz, H-6′), 7.51 (s,1H), 7.40 (d, 1H, J=8.4 Hz, H-5′), 7.17 (dd, 1H, J=8.2 Hz), 7.02 (d, 1H,J=8.2 Hz), 5.82 (s, 1H), 4.01 (s, 3H, OCH₃), 3.57 (t, 2H, J=8.7 Hz),3.36 (t, 2H, J=8.7 Hz), 3.08 (t, 2H, J=6.3 Hz), 2.69 (t, 2H, J=6.3 Hz),2.36 (s, 3H), 1.56 (m, 6H)

Example 923-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-oneshowing following physicochemical property was obtained

Yield: 75%;

m.p: 155° C.;

¹H NMR (CDCl₃): δ ppm 7.85-7.89 (dd, 1H, J=1.8, 8.4 Hz, H-6′), 7.51 (s,1H), 7.40 (d, 1H, J=8.4 Hz, H-5′), 7.17 (dd, 1H, J=8.2 Hz), 7.02 (d, 1H,J=8.2 Hz), 5.83 (s, 1H), 4.01 (s, 3H, OCH₃), 3.50 (t, 2H, J=8.7 Hz),3.30 (t, 2H, J=8.7 Hz), 3.12 (t, 2H, J=6.3 Hz), 2.64 (t, 2H, J=6.3 Hz),2.37 (s, 3H), 1.84 (m, 4H)

Example 933-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dipropylpropanamide

Through similar procedure to the method disclosed in Example 59,3-(2-(3,4-Dimethoxyphenyl)3-(methylthio)benzofuran-5-yl)-N,N-dipropylpropanamideshowing following physicochemical property was obtained

Yield: 84%;

m.p: 116° C.;

¹H NMR (CDCl₃): δ ppm 7.90 (dd, 1H, J=1.8, 8.4 Hz, H-6′), 7.52 (s, 1H),7.41 (d, 1H, J=8.4 Hz, H-5′), 7.17 (dd, 1H, J=8.2 Hz), 6.98 (d, 1H,J=8.2 Hz), 4.00 (s, 3H, OCH₃), 3.95 (s, 3H), 3.28 (t, 2H, J=8.7 Hz),3.08-3.12 (m, 4H), 2.67 (t, 2H, J=8.7 Hz), 3.08-3.15 (m, 4H), 2.66 (t,2H, J=6.3 Hz), 2.37 (s, 3H), 1.49-1.54 (m, 4H), 0.84-0.90 (m, 6H)

Example 943-(2-(3,4-Dmethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(3,4-Dmethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-oneshowing following physicochemical property was obtained

Yield: 78%;

m.p: 124° C.;

¹H NMR (CDCl₃): δ ppm 7.90 (dd, 1H, J=1.8, 8.4 Hz, H-6′), 7.52 (s, 1H),7.41 (d, 1H, J=8.4 Hz, H-5′), 7.17 (dd, 1H, J=8.2 Hz), 6.98 (d, 1H,J=8.2 Hz), 4.00 (s, 3H, OCH₃), 3.95 (s, 3H), 3.57 (t, 2H, J=8.7 Hz),3.36 (t, 2H, J=8.7 Hz), 3.10 (t, 2H, J=6.3 Hz), 2.69 (t, 2H, J=6.3 Hz),2.37 (s, 3H), 1.56 (m, 6H)

Example 953-(2-(3,4-Dmethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(3,4-Dmethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-oneshowing following physicochemical property was obtained

Yield: 79%;

m.p: 117° C.;

¹H NMR (CDCl₃): δ ppm 7.90 (dd, 1H, J=1.8, 8.4 Hz, H-6′), 7.52 (s, 1H),7.41 (d, 1H, J=8.4 Hz, H-5′), 7.17 (dd, 1H, J=8.2 Hz), 6.98 (d, 1H,J=8.2 Hz), 4.00 (s, 3H, OCH₃), 3.95 (s, 3H), 3.49 (t, 2H, J=8.7 Hz),3.31 (t, 2H, J=8.7 Hz), 3.12 (t, 2H, J=6.3 Hz), 2.63 (t, 2H, J=6.3 Hz),2.37 (s, 3H), 1.84 (m, 4H)

Example 962-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 80%;

m.p.: 143.5° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.20 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.11 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 5.85 (bs, 1H),4.40 (d, 1H, 6.3 Hz), 4.00 (s, 3H), 3.92-3.86 (m, 3H), 2.96 (m, 1H),2.59 (m, 1H), 2.34 (s, 3H, SCH₃), 1.57-1.69 (m, 2H), 1.08 (m, 1H),0.88-0.90 (m, 4H)

Example 972-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanoneshowing following physicochemical property was obtained.

Yield: 75%;

m.p.: 82° C.;

¹H NMR (CDCl₃): δ ppm 7:42-7.48 (m, 4H, Ar), 7.20 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.11 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 5.84 (bs, 1H),4.51 (d, 1H, 13.3 Hz), 4.01 (s, 3H), 3.86 (s, 2H), 3.72 (d, 1H, J=13.2Hz), 3.49 (m, 1H), 3.26 (m, 1H), 2.75 (m, 1H), 2.31-2.39 (m, 4H), 1.18(d, 3H, J=6.3 Hz), 1.08 (d, 3H, J=6.3 Hz)

Example 982-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dimethylacetamide

Through similar procedure to the method disclosed in Example 59,2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dimethylacetamideshowing following physicochemical property was obtained.

Yield: 75%;

m.p.: 154.2° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.20 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.11 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 5.89 (bs, 1H),4.00 (s, 3H), 3.84 (s, 2H), 3.05 (s, 3H), 2.99 (s, 3H), 2.35 (s, 3H)

Example 992-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(4-methylpiperazin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(4-methylpiperazin-1-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 65%;

m.p.: 167.9° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.20 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.11 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 5.89 (bs, 1H),4.29 (m, 1H), 4.00 (s, 3H), 3.86 (s, 2H), 3.71-3.75 (m, 2H), 3.48-3.58(m, 2H), 2.35-2.40 (m, 5H), 2.26 (m, 4H), 0.77-0.89 (m, 3H)

Example 100 Methyl2-(2-(4-acetoxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanoate

Through similar procedure to the method disclosed in Example 5, Methyl2-(2-(4-acetoxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanoateshowing following physicochemical property was obtained.

Yield: 55%;

¹H NMR (CDCl₃): δ ppm 7.90-8.01 (m, 3H, Ar), 7.62 (s, 1H), 7.45 (d, 1H,J=8.2 Hz, H-7), 7.25-7.30 (m, 2H), 7.14 (d, 1H, J=8.4 Hz), 3.94 (s, 3H),3.87 (q, 1H, J=6.3 Hz), 3.68 (s, 3H), 2.38 (s, 3H, SCH₃), 2.35 (s, 3H),1.59 (d, 3H, J=6.3 Hz), 1.08 (m, 1H), 0.88-0.90 (m, 4H)

Example 1012-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-oneshowing following physicochemical property was obtained.

Yield: 55%;

m.p.: 168° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 5.88 (bs, 1H),4.00-4.06 (m, 4H), 3.77 (m, 1H), 3.32-3.43 (m, 3H), 2.35 (s, 3H), 1.51(d, 3H, J=6.9 Hz)

Example 102N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanamide

Through similar procedure to the method disclosed in Example 59,N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanamideshowing following physicochemical property was obtained.

Yield: 65%;

m.p.: 200° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 5.88 (bs, 1H),3.93-4.00 (m, 4H), 3.38 (m, 1H), 3.07-3.28 (m, 2H), 2.35 (s, 3H), 1.51(d, 3H, J=6.9 Hz), 1.10 (t, 3H, J=6.9 Hz), 1.01 (t, 3H, J=6.9 Hz)

Example 1032-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(piperidin-1-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 72%;

m.p.: 126° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 3.99 (s, 3H),3.93 (s, 3H), 3.86 (s, 2H), 3.60 (m, 2H), 3.43 (m, 2H), 2.36 (s, 3H),1.36 (m, 2H)

Example 1042-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(pyrrolidin-1-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 80%;

m.p.: 138° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 3.99 (s, 3H),3.93 (s, 3H), 3.78 (s, 2H), 3.50 (m, 4H), 2.37 (s, 3H), 1.89 (m, 4H)

Example 1052-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-morpholinoethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-morpholinoethanoneshowing following physicochemical property was obtained.

Yield: 62%;

m.p.: 155° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 3.99 (s, 3H),3.93 (s, 3H), 3.86 (s, 2H), 3.67 (bs, 4H), 3.50 (bs, 4H), 2.37 (s, 3H)

Example 1062-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 82%;

m.p.: 83° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 4.65 (m, 1H),3.99 (s, 3H), 3.93 (s, 3H), 3.86 (s, 2H), 2.96 (m, 2H), 2.58 (m, 1H),2.36 (s, 3H), 1.53-1.69 (m, 8H), 1.11 (m, 1H), 0.88 (d, 3H, J=6.3 Hz)

Example 1072-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanoneshowing following physicochemical property was obtained.

Yield: 52%;

m.p.: 147° C.;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 4.51 (d, 1H,13.3 Hz), 3.99 (s, 3H), 3.93 (s, 3H), 3.86 (s, 2H), 3.72 (d, 1H, J=13.2Hz), 3.49 (m, 1H), 3.26 (m, 1H), 2.75 (m, 1H), 2.31-2.39 (m, 1H), 1.18(d, 3H, J=6.3 Hz), 1.08 (d, 3H, J=6.3 Hz),

Example 1082-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N-propylacetamide

Through similar procedure to the method disclosed in Example 59,2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N-propylacetamideshowing following physicochemical property was obtained.

Yield: 78%;

¹H NMR (CDCl₃): δ ppm 7.42-7.48 (m, 4H, Ar), 7.21 (dd, 1H, J=1.8, 8.4Hz, H-6), 7.01 (d, 1H, J=8.2 Hz, H-7), 6.96 (S, 1H, H-3), 4.73 (d, 1H,J=6.9 Hz), 3.99 (s, 3H), 3.93 (s, 3H), 3.84 (s, 2H), 2.45-2.93 (m, 4H),2.36 (s, 3H), 1.60-1.77 (m, 4H)

Example 109N,N-Diethyl-3-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)propanamide

Through similar procedure to the method disclosed in Example 13,N,N-Diethyl-3-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)propanamideshowing following physicochemical property was obtained.

Yield: 64%;

m.p.: 164.3° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.44 (m, 4H, Ar), 7.09 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.93 (d, 1H, J=8.2 Hz, H-7), 6.84 (S, 1H, H-3), 3.98 (s, 3H),3.93 (s, 3H), 3.36 (q, 2H, J=6.9 Hz), 3.19 (q, 2H, J=6.9 Hz), 3.05 (t,2H, J=8.4 Hz), 2.65 (t, 2H, J=8.4 Hz), 1.08 (m, 6H)

Example 110N3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-oneshowing following physicochemical property was obtained.

Yield: 54%;

m.p.: 157.2° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.44 (m, 4H, Ar), 7.09 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.93 (d, 1H, J=8.2 Hz, H-7), 6.84 (S, 1H, H-3), 3.99 (s, 3H),3.93 (s, 3H), 3.45 (m, 2H), 3.26 (m, 2H), 3.05 (t, 2H, J=8.4 Hz), 2.62(t, 2H, J=8.4 Hz), 1.77-1.86 (m, 4H)

Example 1113-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-oneshowing following physicochemical property was obtained.

Yield: 65%;

m.p.: 129.6° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.44 (m, 4H, Ar), 7.09 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.93 (d, 1H, J=8.2 Hz, H-7), 6.85 (S, 1H, H-3), 3.99 (s, 3H),3.93 (s, 3H), 3.57 (m, 2H), 3.33 (m, 2H), 3.06 (t, 2H, J=8.4 Hz), 2.70(t, 2H, J=8.4 Hz), 1.43-1.59 (m, 6H)

Example 1123-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-morpholinopropan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-morpholinopropan-1-oneshowing following physicochemical property was obtained.

Yield: 58%;

m.p.: 139.2° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.44 (m, 4H, Ar), 7.09 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.93 (d, 1H, J=8.2 Hz, H-7), 6.85 (S, 1H, H-3), 3.99 (s, 3H),3.93 (s, 3H), 3.61 (bs, 4H), 3.47 (m, 2H), 3.35 (m, 2H), 3.06 (t, 2H,J=8.4 Hz), 2.70 (t, 2H, J=8.4 Hz)

Example 1133-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)propan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(2S,6R)-2,6-dimethylmorpholino)propan-1-oneshowing following physicochemical property was obtained.

Yield: 59%;

m.p.: 163.2° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.44 (m, 4H, Ar), 7.09 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.93 (d, 1H, J=8.2 Hz, H-7), 6.85 (S, 1H, H-3), 4.46 (d, 1H,13.3 Hz), 3.99 (s, 3H), 3.93 (s, 3H), 3.86 (s, 2H), 4.45-4.53 (m, 3H),3.23 (m, 1H), 2.62-3.08 (m, 7H), 2.27 (m, 1H), 1.18 (d, 3H, J=6.3 Hz),1.08 (d, 3H, J=6.3 Hz)

Example 1142-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 59%;

m.p.: 151° C.;

¹H NMR (CDCl₃): δ ppm 7.35-7.44 (m, 4H, Ar), 7.13 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.98 (d, 1H, J=8.2 Hz, H-7), 6.82 (S, 1H, H-3), 5.78 (s, 1H),4.00 (s, 3H), 3.81 (s, 2H), 3.58 (m, 2H), 3.41 (m, 2H), 1.55 (m, 2H),1.33-1.35 (m, 3H)

Example 1152-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 65%;

m.p.: 193° C.;

¹H NMR (CDCl₃): δ ppm 7.35-7.44 (m, 4H, Ar), 7.13 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.98 (d, 1H, J=8.2 Hz, H-7), 6.82 (S, 1H, H-3), 5.82 (s, 1H),4.00 (s, 3H), 3.82 (s, 2H), 3.43-3.53 (m, 4H), 1.81-1.91 (m, 4H)

Example 116N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)acetamide

Through similar procedure to the method disclosed in Example 59,N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)acetamideshowing following physicochemical property was obtained.

Yield: 73%;

m.p.: 180° C.;

¹H NMR (CDCl₃): δ ppm 7.35-7.44 (m, 4H, Ar), 7.13 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.98 (d, 1H, J=8.2 Hz, H-7), 6.82 (S, 1H, H-3), 5.84 (s, 1H),3.99 (s, 3H), 3.78 (s, 2H), 3.30-3.49 (m, 4H), 1.07-1.16 (m, 6H)

Example 1172-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dipropylacetamide

Through similar procedure to the method disclosed in Example 59,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dipropylacetamideshowing following physicochemical property was obtained.

Yield: 77%;

m.p.: 122° C.;

¹H NMR (CDCl₃): δ ppm 7.35-7.44 (m, 4H, Ar), 7.13 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.98 (d, 1H, J=8.2 Hz, H-7), 6.82 (S, 1H, H-3), 5.84 (s, 1H),4.00 (s, 3H), 3.78 (s, 2H), 3.19-3.33 (m, 4H), 1.25-1.61 (m, 4H),0.85-0.90 (m, 6H)

Example 1182-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)ethanoneshowing following physicochemical property was obtained.

Yield: 78%;

m.p.: 189° C.;

¹H NMR (CDCl₃): δ ppm 7.35-7.44 (m, 4H, Ar), 7.13 (dd, 1H, J=1.8, 8.4Hz, H-6), 6.98 (d, 1H, J=8.2 Hz, H-7), 6.82 (S, 1H, H-3), 5.80 (s, 1H),4.50 (m, 1H), 4.00 (s, 3H), 3.81 (s, 2H), 3.72 (m, 1H), 3.48 (m, 1H),3.23 (m, 1H), 2.73 (m, 1H), 2.33 (m, 1H), 1.18 (d, 3H, J=6.3 Hz), 1.08(d, 3H, J=6.3 Hz)

Example 1191-(4-Benzylpiperidin-1-yl)-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)ethanone

Through similar procedure to the method disclosed in Example 78,1-(4-Benzylpiperidin-1-yl)-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 73%;

m.p.: 198° C.;

¹H NMR (CDCl₃): δ ppm 7.43-7.45 (m, 2H, Ar), 7.25-7.39 (m, 2H),7.22-7.27 (m, 3H), 7.14 (dd, 1H, J=1.8, 8.4 Hz), 6.97 (d, 1H, J=8.4 Hz,H-7), 6.82-6.90 (m, 4H), 4.00 (s, 3H), 3.80-3.87 (m, 4H), 3.64 (m, 2H),3.14 (m, 2H), 2.97 (m, 2H), 1.28 (m, 2H), 0.86 (m, 1H)

Example 1202-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(4-phenylpiperazin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(4-phenylpiperazin-1-yl)ethanoneshowing following physicochemical property was obtained.

Yield: 74%;

m.p.: 145° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H), 6.98 (d,1H, J=8.4 Hz), 6.82 (s, 1H), 4.68 (m, 1H), 4.01 (s, 3H), 3.85 (m, 1H),3.80 (s, 2H), 3.74 (m, 1H), 2.89 (m, 1H), 2.48-2.52 (m, 3H), 1.85 (m,1H)

Example 121 Methyl2-(2-(4-acetoxy-3-methoxyphenyl)benzofuran-5-yl)propanoate

Through similar procedure to the method disclosed in Example 5, Methyl2-(2-(4-acetoxy-3-methoxyphenyl)benzofuran-5-yl)propanoate showingfollowing physicochemical property was obtained.

Yield: 76%;

¹H NMR (CDCl₃): 5 ppm 7.38-7.50 (m, 4H, Ar), 7.20-7.24 (m, 2H), 7.09 (d,1H, J=8.4 Hz), 6.94 (s, 1H), 3.91 (s, 3H), 3.80 (q, 1H, J=6.3 Hz), 3.66(s, 3H), 2.32 (s, 3H), 1.55 (d, 3H, J=6.3 Hz)

Example 1222-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-oneshowing following physicochemical property was obtained.

Yield: 76%;

m.p.: 199° C.;

¹H NMR (CDCl₃): 5 ppm 7.35-7.43 (m, 4H, Ar), 7.13 (d, 1H, J=8.4 Hz),6.98 (d, 1H, J=8.4 Hz), 6.82 (s, 1H), 5.78 (bs, 1H), 3.93-4.00 (m, 5H),3.74 (m, 1H), 3.32-3.46 (m, 4H), 1.48 (d, 3H, J=6.9 Hz), 1.25-1.29 (m,4H)

Example 1232-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)propan-1-oneshowing following physicochemical property was obtained.

Yield: 79%;

m.p.: >200° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H), 4.64 (m,1H), 3.74-4.00 (m, 5H), 2.91 (m, 1H), 2.50-2.62 (m, 2 μl), 1.25-1.59 (m,4H), 0.93 (d, 3H, J=6.6 Hz), 0.73 (d, 3H, J=6.6 Hz)

Example 1242-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-morpholinopropan-1-one

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-morpholinopropan-1-oneshowing following physicochemical property was obtained.

Yield: 63%;

m.p.: 188° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H), 3.99 (s,3H), 3.93 (q, 1H, J=6.6 Hz), 3.62-3.83 (m, 2H), 3.37-3.57 (m, 6H), 1.50(d, 3H, J=6.9 Hz)

Example 125N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)propanamide

Through similar procedure to the method disclosed in Example 59,N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)propanamideshowing following physicochemical property was obtained.

Yield: 73%;

m.p.: 192° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H), 5.76 (s,1H), 4.00 (s, 3H), 3.91 (q, 1H), 3.50 (m, 1H), 3.48-3.11 (m, 3H), 1.48(d, 3H), 1.09 (t, 3H), 0.99 (t, 3H, J=6.3 Hz)

Example 1262-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dimethylpropanamide

Through similar procedure to the method disclosed in Example 59,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dimethylpropanamideshowing following physicochemical property was obtained.

Yield: 66%;

m.p.: 173° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H), 5.76 (s,1H), 4.00 (s, 3H), 3.47 (q, 1HJ=6.9 Hz), 2.97 (s, 3H), 2.92 (s, 3H),1.48 (d, 3H, J=6.3 Hz)

Example 1272-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dipropylpropanamide

Through similar procedure to the method disclosed in Example 59,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dipropylpropanamideshowing following physicochemical property was obtained.

Yield: 73%;

m.p.: 160° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H),3.89-4.00 (m, 4H), 3.46 (m, 1H), 3.29 (m, 1H), 2.93-3.15 (m, 2H),1.25-1.55 (m, 5H), 0.84 (q, 6H, J=7.5 Hz)

Example 1282-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)propan-1-one

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-((2S,6R)-2,6-dimethylmorpholino)propan-1-oneshowing following physicochemical property was obtained.

Yield: 53%;

m.p.: 115° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H), 5.76 (s,1H), 4.54 (m, 1H), 4.01 (s, 3H), 3.90 (m, 1H), 3.72 (m, 1H), 3.45-3.80(m, 2H) 2.70 (m, 1H), 2.32 (m, 1H) 1.56 (d, 3H, J=6.3 Hz), 1.18 (d, 3H,J=6.3 Hz), 1.08 (d, 3H, J=6.3 Hz)

Example 1292-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)propan-1-oneshowing following physicochemical property was obtained.

Yield: 77%;

m.p.: 172° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H), 4.00 (s,3H), 3.80 (q, 1H, J=6.6 Hz), 3.21-3.56 (m, 4H), 1.76-1.-89 (m, 4H), 1.26(d, 3H, J=6.9 Hz)

Example 1302-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N-propylpropanamide

Through similar procedure to the method disclosed in Example 59,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N-propylpropanamideshowing following physicochemical property was obtained.

Yield: 89%;

m.p.: 146.9° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.43 (m, 4H, Ar), 7.06-7.23 (m, 5H), 5.78 (s,1H), 5.33 (bs, 1H), 4.01 (s, 3H), 3.64 (q, 1H), 3.15 (q, 2H), 1.57 (d,3H), 1.41 (m, 2H), 0.80 (t, 3H,)

Example 131N,N-Diethyl-2-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)acetamide

Through similar procedure to the method disclosed in Example 59,N,N-Diethyl-2-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)acetamide showingfollowing physicochemical property was obtained.

Yield: 77%;

m.p.: 134° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.45 (m, 4H, Ar), 7.14 (d, 1H, J=8.4 Hz),6.90 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 3.99-3.93 (s, 3H), 3.78 (s, 2H),3.30-3.47 (m, 4H), 1.02-1.16 (d, 6H)

Example 1322-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)ethanoneshowing following physicochemical property was obtained

Yield: 77%;

m.p.: 115° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.45 (m, 4H, Ar), 7.14 (d, 1H, J=8.4 Hz),6.90 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 4.60 (d, 1H), 3.99 (s, 3H), 3.94(s, 3H), 3.81 (s, 2H), 3.57-3.63 (m, 2H), 3.38-3.48 (m, 2H), 1.48-1.72(m, 4H), 1.3-1.4 (m, 2H)

Example 1332-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperidin-1-yl)ethanoneshowing following physicochemical property was obtained

Yield: 77%;

m.p.: 139° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.45 (m, 4H, Ar), 7.14 (d, 1H, J=8.4 Hz),6.90 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 4.60 (d, 1H), 3.99 (s, 3H), 3.94(s, 3H), 3.81 (s, 2H), 2.94 (t, 1H), 2.98 (t, 1H), 1.47-1.72 (m, 5H),1.00-1.03 (m, 1H), 0.88 (d, 3H)

Example 1342-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-morpholinoethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-morpholinoethanoneshowing following physicochemical property was obtained

Yield: 77%;

m.p.: 130° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.45 (m, 4H, Ar), 7.14 (d, 1H, J=8.4 Hz),6.90 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.82(s, 2H), 3.66 (s, 4H), 3.48 (s, 4H)

Example 1352-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-N,N-dimethylacetamide

Through similar procedure to the method disclosed in Example 59,2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-N,N-dimethylacetamide showingfollowing physicochemical property was obtained

Yield: 77%;

m.p.: 175° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.45 (m, 4H, Ar), 7.14 (d, 1H, J=8.4 Hz),6.90 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.80(s, 2H), 3.03 (s, 3H), 2.98 (s, 3H)

Example 1362-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(pyrrolidin-1-yl)ethanoneshowing following physicochemical property was obtained

Yield: 77%;

m.p.: >200° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.45 (m, 4H, Ar), 7.14 (d, 1H, J=8.4 Hz),6.90 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 3.74 (s, 2H), 3.43-3.53 (m, 4H),1.81-1.96 (m, 4H)

Example 1371-(4-Benzylpiperidin-1-yl)-2-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)ethanone

Through similar procedure to the method disclosed in Example 78,1-(4-Benzylpiperidin-1-yl)-2-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)ethanoneshowing following physicochemical property was obtained

Yield: 77%;

m.p.: 115° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.45 (m, 4H, Ar), 7.14 (d, 1H, J=8.4 Hz),6.90 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 4.57-4.72 (m, 1H), 3.99 (s, 3H),3.94 (s, 3H), 3.83 (s, 2H), 3.80 (s, 2H), 2.83 (m, 1H), 2.42-2.60 (m,4H), 2.00 (s, 1H), 1.60-1.73 (m, 2H)

Example 1382-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperazin-1-yl)ethanone

Through similar procedure to the method disclosed in Example 78,2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-1-(4-methylpiperazin-1-yl)ethanoneshowing following physicochemical property was obtained

Yield: 77%;

m.p.: 130° C.;

¹H NMR (CDCl₃): δ ppm 7.36-7.45 (m, 4H, Ar), 7.14 (d, 1H, J=8.4 Hz),6.90 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 3.68 (t, 2H), 3.50 (t, 2H), 2.36(t, 2H), 2.19-2.24 (m, 5H),

Example 1393-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-one

Through similar procedure to the method disclosed in Example 78,3-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-1-(piperidin-1-yl)propan-1-oneshowing following physicochemical property was obtained

Yield: 77%;

m.p.: 197° C.;

¹H NMR (CDCl₃): δ ppm 7.38 (t, 4H, Ar), 7.10 (d, 1H, J=8.4 Hz), 6.90 (d,1H, J=8.4 Hz), 6.81 (s, 1H), 6.04 (s, 1H), 4.11 (s, 1H), 3.56 (t, 2H,J=8.7 Hz), 3.33 (t, 2H, J=8.7 Hz), 3.05 (t, 2H, J=6.9 Hz), 2.66 (t, 2H,J=6.9 Hz), 1.52 (m, 6H),

Example 1402-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanoic acid

Through similar procedure to the method disclosed in Example 70,2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)propanoic acidshowing following physicochemical property was obtained

Yield: 75%;

m.p.: >200° C.;

¹H NMR (CD₃OD): δ ppm 7.98 (d, 1H, J=1.8 Hz), 7.88 (dd, 1H, J=1.8, 8.4Hz), 7.62 (d, 1H, J=1.8 Hz), 7.47 (d, 1H, J=8.4 Hz), 7.29 (dd, 1H,J=1.8, 8.4 Hz), 7.08 (d, 1H, J=8.4 Hz), 3.92 (s, 3H), 3.90 (s, 3H), 3.85(q, 1H, J=6.9 Hz) 2.37 (s, 3H), 2.52 (d, 3H, J=6.9 Hz)

Example 141 N-[2-(3,4-Dimethoxy-phenyl)-benzofuran-5-yl]-propionamide

Through similar procedure to the method disclosed in Example 59,N-[2-(3,4-Dimethoxy-phenyl)-benzofuran-5-yl]-propionamide showingfollowing physicochemical property was obtained

Yield: 79%;

m.p: 187° C.;

¹H NMR (CDCl₃): δ ppm 7.88 (s, 1H), 7.42 (d, 2H, J=8.6 Hz), 7.35 (d, 1H,J=1.7 Hz), 7.20 (dd, 1H, J=8.6 Hz, J=1.8 Hz), 6.94 (d, 1H, J=8.4 Hz),6.86 (s, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.42 (m, 2H), 1.28 (t, 3H,J=7.5 Hz)

Example 142 N-[2-(3,4-Dimethoxy-phenyl)-benzofuran-5-yl]-butyramide

Through similar procedure to the method disclosed in Example 59,N-[2-(3,4-Dimethoxy-phenyl)-benzofuran-5-yl]-butyramide showingfollowing physicochemical property was obtained

Yield: 55%;

m.p: >200° C.;

¹H NMR (CDCl₃): δ ppm 7.89 (s, 1H), 7.42 (d, 2H, J=8.6 Hz), 7.36 (d, 1H,J=2.0 Hz), 7.20 (m, 1H), 6.94 (d, 1H, J=8.3 Hz), 6.87 (s, 1H), 3.99 (s,3H), 3.94 (s, 3H), 2.37 (t, 2H, J=7.3 Hz), 1.80 (m, 2H), 1.04 (t, 3H,J=7.4 Hz)

Example 143 2-(3,4-dimethoxyphenyl)-N-propylbenzofuran-5-amine

Through similar procedure to the method disclosed in Example 59,2-(3,4-dimethoxyphenyl)-N-propylbenzofuran-5-amine showing followingphysicochemical property was obtained

Yield: 44%;

m.p: 88° C.;

¹H NMR (CDCl₃): δ ppm 7.39 (dd, 1H, J=8.2 Hz, J=1.8 Hz), 7.34 (d, 1H,J=2.0 Hz), 7.30 (d, 1H, J=8.8 Hz), 6.91 (d, 1H, J=8.4 Hz), 6.78 (s, 1H),6.73 (d, 1H, J=2.4 Hz), 6.58 (dd, 1H, J=8.6 Hz, J=2.4 Hz), 3.98 (s, 3H),3.92 (s, 3H), 3.11 (t, 2H, J=7.0 Hz), 1.69 (m, 2H), 1.03 (t, 3H, J=7.5Hz)

MS (FAB) m/z 311 (M+H)

Example 144 Butyl-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-amine

Through similar procedure to the method disclosed in Example 59,Butyl-[2-(3,4-dimethoxy-phenyl)-benzofuran-5-yl]-amine showing followingphysicochemical property was obtained

Yield: 18%;

¹H NMR (CDCl₃): δ ppm 7.40 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.35 (d, 1H,J=2.0 Hz), 7.30 (d, 1H, J=8.6 Hz), 6.92 (d, 1H, J=8.4 Hz), 6.79 (s, 1H),6.73 (d, 1H, J=2.4 Hz), 6.59 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 3.99 (s, 3H),3.93 (s, 3H), 3.15 (t, 2H, J=7.0 Hz), 1.53 (m, 4H), 0.98 (t, 3H, J=7.3Hz)

MS (FAB) m/z 325 (M+H)

Example 145 5-Allyloxy-2-(3,4-dimethoxy-phenyl)-benzofuran

Through similar procedure to the method disclosed in Example 70,5-Allyloxy-2-(3,4-dimethoxy-phenyl)-benzofuran showing followingphysicochemical property was obtained

Yield: 21%;

m.p: 118° C.;

¹H NMR (CDCl₃): δ ppm 7.39 (m, 3H), 7.04 (d, 1H, J=2.6 Hz), 6.94 (d, 1H,J=8.3 Hz), 6.89 (dd, 1H, J=8.8 Hz, J=2.6 Hz), 6.85 (s, 1H), 6.11 (m,1H), 5.43 (m, 1H), 5.30 (m, 1H), 4.57 (m, 1H), 3.99 (s, 3H), 3.93 (s,3H)

Example 146 52-(3,4-Dimethoxy-phenyl)-5-propoxy-benzofuran

Through similar procedure to the method disclosed in Example 70,2-(3,4-Dimethoxy-phenyl)-5-propoxy-benzofuran showing followingphysicochemical property was obtained

Yield: 4%;

m.p: 114° C.;

¹H NMR (CDCl₃): δ ppm. 7.88 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.68 (d, 1H,J=2.0 Hz), 7.35 (m, 1H), 7.02 (d, 1H, J=8.6 Hz), 6.96 (d, 1H, J=8.6 Hz),6.77 (m, 2H), 3.93 (m, 8H), 1.82 (m, 2H), 1.04 (t, 3H, J=7.3 Hz)

Experimental Example 1 In Vitro Activity Test

1-1. Inhibition Test of Beta Amyloid Aggregation

Synthetic beta amyloid 1-42 (BACHEM) was dissolved in DMSO in order to250 μm solution and diluted with PBS into 1/10 on fluorescent blackplate to induce aggregation. By comparing with inhibition activity ofthe tanshinone compounds prepared in Example 1 on beta amyloidaggregation, the test sample showing more than 50% inhibition activityat 10 μg/ml was chosen to use and added to react for 1 hour at roomtemperature. ThT (Thioflavin T) was diluted with 50 mM glycine buffersolution and the diluted solution was added to each well by 150 μl/well.The absorbance was determined by microplate reader (SAFIRE, TECAN) at450 nm excitation wavelength/480 nm emission wavelength and theinhibition activity of the test sample on beta amyloid aggregation wastransformed into IC₅₀.

As can be shown in FIG. 1, the compound 18b (Example 28) showed mostpotent inhibitory effect on the aggregation of beta amyloid.

1-2. Inhibition Test of Beta Amyloid Aggregation Lysis

Synthetic beta amyloid, Ab(1-42) [Bachem Cat. No. H1368;H-Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-ILe-Ala-OH])was dissolved in DMSO in order that it induces aggregation at theconcentration of 25 microM for 1 week. The test group added withaggregated betaamyloid and test samples inhibiting the inhibition ofaggregation and a control group added with only A were reacted togetherat room temperature for 1 hour on fluorescent black plate. ThT(Thioflavin T) was diluted with 50 mM glycine buffer solution to be 5microliter and the diluted solutions were added to each well by 150μg/well. The fluorescence intensity of each group was determined bymicroplate reader (SAFIRE, TECAN) at 450 nm excitation wavelength/480 nmemission wavelength after shaking together for 10 seconds.

1-3. Inhibition Test of Beta Amyloid Toxicity

To determine the inhibitory activity of the compounds prepared inExamples on beta-amyloid toxicity, following test was performedaccording to the procedure disclosed in the literature (Gillardon, F. etal., Brain Research, 706 (1), pp. 169-172, 1996).

HT22 mouse neuronal cell line was incubated in DMEM (Dulbecco's ModifiedEagle's Medium, Gibco-BRL) medium supplemented with 10% FBS (FetalBovine Serum, Hyclone) and 1% penicillin/streptomycin (Sigma Co.). Priorto test, HT22 cell was incubated on 96 well plates with a density of5×10³ cell/well and further incubated in serum free DMEM medium for 1hour before the treatment of test sample. Various concentration ofcompounds prepared in Examples used as a test sample was added theretoand incubated for 1 hour. Aggregated beta amyloid 25-35 (US peptide) wastreated thereto to the concentration of 25 μm and incubated for 18 hoursto induce cell necrosis. 5 mg/ml of MIT(3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide)solution was added each well with 15 μl/well and the well was incubatedfor 4 hours. Dissolving buffer solution (10% SDS, 50% dimethylformamide, pH 4.7) was added to each well with 100 μl/well and reactedfor overnight. 18 hours after the reaction, the absorbance of solutionwas determined by microplate reader (SAFIRE, TECAN) at 570 nm/630 nmwavelength (Gillardon, F. et al., Brain Research, 706 (1) pp 169-172,1996).

1-4. Determination of Cytotoxicity

To determine the toxicity of test sample, HT22 cell was incubated inaccordance with similar method disclosed in 1-3 and variousconcentration of the test sample prepared in Examples 1-89 was added tothe cell to incubate for 18 hours. MTT solution and Dissolving buffersolution was added to cell serially and the absorbance was determined bymicroplate reader (SAFIRE, TECAN) at 570 nm.

As can be shown in FIG. 1, the compounds 15a, 15b, 16 and 18b showedpotent inhibition effect on the beta-amyloid aggregation andbeta-amyloid toxicity, particularly, compound 18b (Example 28) amongthem showed most potent inhibitory effect on the aggregation of betaamyloid and potent solubilizing activity of beta-amyloid.

Experimental Example 2 In Vivo Activity Test

Experimental Design

For passive avoidance test, male ICR mouse weighing 25 g purchased fromSamtaco Co. was bred with five mice per cage and the cage was kept withfollowing condition maintaining the temperature of 22±2° C. and therelative humidity of 50±5% under the regularly controlled light/darkcondition with an interval of 12 hours.

Synthetic beta amyloid 1-42 (BACHEM) was dissolved in DMSO in order tobe 250 μm solution and diluted with PBS to 10 nM and aggregated at 37°C. for four days (Passive Avoidance test) or six days (Y maze test).

Aggregated beta amyloid 1-42 was administrated into the mice accordingto the procedure disclosed in the literature (Lausen & Belknap, J.Pharmacol. Methods, 16 pp 355-357, 1986).

50 μl of aggregated beta amyloid 1-42 was administrated into the 2.4 mmdepth of bregma region with 50 μl of Hamilton micro-syringe equippedwith 26-gauge needle. The behavior tests were divided into Y maze testand PA (passive avoidance) test after the beta amyloid administration. Ymaze test was performed 2 days after the administration and PA test was3 days after the administration. Each test was done with more than 10mice.

At the end of the experiment, the brain of animals was delivered andkept in 10% formalin solution to staining.

Drug Treatment

After the administration of beta amyloid, the test compounds, i.e., 15a,15b, 16 and 18b prepared in Examples were administrated into the mice atthe interval of once a day in case of Y maze test and the test sampleswere continuously administrated for three days in case of passiveavoidance test. The concentration test samples in orally administrationgroup was set to 100 mg/kg treatment group and especially, the variousconcentrations of compound 18b, 50 mg/kg, 100 mg/kg, and 200 mg/kg wereadopted to determine its drug dose-dependency. In case of Y maze test,the feed was administered using by pellet feed for 8 days and one amongthose pellet was designed to containing 3 mg of drug.

Behavior Procedure

AD Acute Model Experiment—Y Maze Test

To test the cognitive capacity effects of the four compounds, i.e.,compounds 15a, 15b, 16, and 18b, selected from Experimental Example 1,following Y maze test was performed according to the procedure disclosedin the literature (Psychopharmacology, 94, pp. 491-95, 1998).

The Y-maze test was performed two days after the administration ofbeta-amyloid. Y-maze box was made of black acrylic and was composed ofthree arms (length: 40 cm, Height: 10 cm, Width 5 cm) having identicalangle each other. The mice were positioned at the center of the maze andlet to move freely within the maze for eight minutes. Thereafter, theentering order of the mice into the pathway was observed and theentering time was determined when four limbs of the mice were enteredwithin the pathway. To determine the spatial memory, the percentage ofspontaneous alteration behavior was calculated by applying the measuredalteration frequency to following empirical formula 1 and the frequencyof actual alteration behavior was assigned once at the time that themice had entered the three pathways continuously.Spontaneous alteration(%)=[actual alteration/total armentries−2]×100  [Math Formula 1]

FIG. 2 indicates the result of the Y maze test with the four compoundsselected from Experimental Example 1 (See FIG. 2).

As can be seen in FIG. 2, the compound 18b shows potent recoveringeffect on memory learning capacity damaged by beta-amyloid in a dosedependent manner. Also FIG. 3 shows that the recovering effect of thecompound was increased in a dose-dependent manner. The treatment groupwith more than 100 mg/kg showed the most excellent effect on the memorylearning capacity (See FIG. 3).

2-2-2. AD Acute Model Experiment—Passive Avoidance Test

To test the cognitive capacity effects of the four compounds, i.e.,compounds 15a, 15b, 16, and 18b, selected from Experimental Example 1,following Passive Avoidance test was performed according to theprocedure disclosed in the literature (J. Neurochem., 71, pp. 875-878,1998).

Three days after the beta-amylaid administration, the passive avoidancetest was performed by determining the time until every mouse enteredinto the dark compartment from the light compartment (step-throughlatency). The passive avoidance box was divided into two compartments,i.e., one is white chamber and another is dark chamber equipped with agrid floor providing an inescapable shock.

During the first acquisition trial, each mouse was placed in the lightedcompartment; as soon as they entered the dark compartment, the door wasclosed, and they received an electric shock through the grid floor (0.6Ma, 3 s). Thereafter, the mice were transferred to their home cage. 24hours after the training trial, the mice were again placed in thelighted compartment and the time until they re-entered the darkcompartment was measured (step-through latency). At this trial, the cutoff latency was set to 300 seconds.

At the result of the above-describe test, the compound 18b exhibitedpotent recovering effect on memory learning damaged by beta-amyloid (SeeFIG. 4). Also FIG. 3 shows that the recovering effect of the compoundwas increased in a dose-dependent manner. The treatment group with morethan 100 mg/kg showed the most excellent effect on the memory learningcapacity (See FIG. 5).

Water Maze Test

To test the cognitive capacity effects of two compounds, i.e., compounds15a and 18b selected from Experimental Examples, following water mazetest was performed according to the procedure disclosed in theliterature (J. Neurosci. Methods., 11, pp. 47-60, 1984).

The water maze test was performed with using round aquarium. Thetemperature of water in the aquarium was maintained at 23° C. and theheight of the water was arranged to be 1 cm higher than the level ofplatform. The platform was placed in the middle of one among 4 arbitraryquadrants in the aquarium and skim milk powder was poured into the waterin order that the mouse could not show the platform. The spatialevidence for searching platform position was given to the mice at thewall surfaces surrounding the aquarium and the test was performed.

The test was performed continuously for 5 days four times a day and theinterval of each trial was set to 30 seconds. During each trial, themice was let to start randomly from four starting points and the time(latency) until they found the hidden platform for 60 seconds wasmeasured. Noldus program (Etho vision software) was used as a trackingsystem.

As can be seen in FIG. 6, it has confirmed that the memory learningcapacity in the mice where beta-amyloid was injected into a ventricle oftheir brains was decreased (See FIG. 6).

As can be seen in FIG. 7, it showed the result of the memory learningcapacity in the mice treated with the inventive compounds 15a and 18b(See FIG. 7).

It has been confirmed that the inventive compounds recovered thedecreased memory learning capacity in vivo in the mice treatedbeta-amyloid, of which result was consistent with the results ofinhibition test of beta-amyloid aggregation and beta-amyloid toxicitytest in vitro.

2-3-4 Cognitive Capacity Test

To test the cognitive capacity effects of four compounds, i.e.,compounds 15a, 15b, 16 and 18b selected from Experimental Examples,following cognitive capacity test was performed according to theprocedure disclosed in the literature (Behav. Brain Res., 31, pp. 47-59.1988)

The cognitive capacity test was performed by using an open field boxconsisting of black acrylic 50×50×30(height) and the identical twoobjects which showed similar preference between each other were placedat 5 cm far away from the walls in a opposite direction.

The mice were allowed to explore the box for 3 minutes three timesbefore testing (adaptive training). During training, the exploring timeto find two objects placed in the box was determined for 3 minutes. Intesting phase after 24 hours, one of the two objects was changed to newobject and then the exploration time was measured again for 3 minutes inthe box. Exploration behavior was calculated by following Math formula 2and defined as follow: touching the object or sniffing it with puttingtheir heads at a distance=2 cm to the objects.Preference index=exploration time for new object/exploration time fortotal object  [Math Formula 2]

As the result of the above test, it has confirmed that the group treatedwith the inventive compounds increased memory-learning capacityresulting in increased preference index while the group treated withbeta amyloid could not concentrate on either object or could not becurious on new object. (See FIG. 8).

2-4. Immunochemistry Staining of AD Acute Model Mouse RecoveringCognitive Capacity

2-4-1. Brain Delivery and Pretreatment Before Staining

At the end of behavior test, the mouse brain was delivered, kept in 10%formalin solution for 24 hours and transferred to 30% sucrose solution.After fixing the brain, the brain was performed to coronal section witha width of 40 micrometer using by cryostat. The sliced brain wasperformed to staining with cresyl violet to confirm the injury of brainneuronal cell, with ChAT to confirm the injury of cholinergic neuron andwith GFAP to confirm the activation of astrocytes.

2-4-2. Cresyl Violet Staining

After the tissue was placed on gelatin-coated slide to stain with Cresylviolet, the tissue was performed to dehydration using ethanol. Thetissue was incubated for about 3 minutes and dipped into 0.5% CresylViolet solution for 30 mins. After the solution was performed tore-hydration with ethanol, the slice was dipped into xylene for 3minutes. The dried tissue was fixed with Canada balsam mounting medium.

2-4-3. Immunohistochemistry

In the washing process between all the antibody incubation, PBST wasused to wash the tissues. To reduce the activity of endogenousperoxidase enzyme, the tissue was pre-treated with 0.5% H₂O₂ and thentreated with 5% FBS at room temperature for 1 hour to removenon-specific binding. The tissue was incubated at 4° C. for overnightusing by mouse anti-GFAP (1:200) monoclonal antibody and goat-anti-ChAT(1:200) polyclonal antibody. A horse radish peroxidase-conjugatedanti-mouse IgG and anti-goat IgG secondary antibody (1:600) wereincubated at room temperature for 1 hour and detected by DAB kit afterthe incubation.

To observe the neuronal injury and recovery, NeuN staining wasperformed, and GFAP staining was performed to observe the activation ofastrocytes. ChAT staining was performed to observe to observe the injuryand recovery of cholinergic neuron and the results were shown in FIGS. 9to 11.

As can be shown in FIG. 9, it has been confirmed that the density ofneuronal cell at CA region in Hippocampus was increased in case that thememory learning capacity was recovered by treatment with inventivecompounds in learning memory-injured mouse model caused by beta-amyloidtreatment.

FIG. 10 showed that the group treated with the inventive compoundsreduced the activation of astrocytes and the memory learning recoveredgroup increased the area of cholinergic neuron as shown in FIG. 11.

Experimental Example 3 In Vivo Physiological Activity

3-1. Experimental Design

13 months old dementia model male mice expressing APPswe was used in theexperiment and the mice was divided into two groups, i.e., control groupconsisting of 2 mice and test groups consisting of 4 mice. Each mousehad been fed with the feed mixed with 3 mg of compound 11b everyday for4 months.

3-2. Behavior Procedure

3-2-1. Y Maze Test

To test the cognitive capacity effects of the compound 11b chosen fromthe result of Experimental Example 1, following Y maze test wasperformed according to the procedure disclosed in the literature(Psychopharmacology, 94, pp 491-95, 1998).

From two days after the administration of beta-amyloid, the Y-maze testwas performed. Y-maze box was made of black acrylic and composed ofthree arms (length: 40 cm, Height: 10 cm, Width 5 cm) having identicalangle each other. The mice were positioned at the center of the maze andlet to move freely in the maze for eight minutes. Thereafter, theentering order of the mice into the pathway was observed and theentering time was determined when four limbs was entered within thepathway. To determine the spatial memory, the percentage of spontaneousalteration behavior was calculated by applying measured alterationfrequency to following math formula 1 and the frequency of actualalteration behavior was assigned once at the time that the mice hadentered the three pathways continuously.

As can be seen in FIG. 12, the transgenic mice treated with compound 11bshowed more increased curiosity about new object than control group (SeeFIG. 12).

3-2-2. Inhibitory Activity of Beta Amyloid Plaque Formation

(a). Brain Delivery Using RIPA (Radio Immuno Precipitation Assay) BufferSolution

At the end of behavior test, the brain of mouse was delivered and theleft hemisphere was frozen to be used as a cryo-section material. Theremaining right hemisphere was used to measure the formation ofbeta-amyloid according to the procedure disclosed in the literature (J.Neurosci, 21 (12), pp 4183-4187, 2001).

For obtaining RIPA buffer soluble faction, the half brain of a mouse wasmacerated with ultrasonic waves (2×25 struck, output 20%) in 1 ml ofRIPA buffer containing 150 mg/ml protease inhibitor cocktail and thetissues were centrifuged at 20.000 g for 5 minutes.

(b). ELISA Analysis

The amount of beta-amyloid in the brains of mice was determined byAβ-specific ELISA method according to the manual provided from BiosourceCo and ELISA kit (KHB 3482, Biosource Co.) was used in the experiment.Ab(1-40 & 42) provided as standard peptides was dissolved in givenbuffer solution (55 mM sodium bicarbonate. pH 9.0) and diluted toseveral concentrations ranging from 0 to 1000 pg/ml to obtaincalibration curve. 25 g or 50 g of the delivered brain from the micewere diluted to 100 μl with dilution buffer and the diluted brains wereadded to ELISA strip. After incubation for 2 hours, each well was washed4 times with wash buffer and detecting antibody was added to each wellto incubate for 2 hours. After the incubation, all the wells were washed4 times again and the secondary antibody formed by HRP polymer was addedthereto to incubate for 2 hours. The incubated wells were washed fivetimes and stabilized chromogen was added thereto to induce colorreaction. After 30 minutes, stop solution was added to each well to stopthe reaction. The level of color reaction was determined at 450 nm usingby spectrophotometer and the absolute amount of beta-amyloid in thesamples was transformed by comparing with standard value. The brain ofthe mice treated with the compound 18b for 4 months was delivered andthe amount of beta-amyloid in supernatant obtained from the dissolvedbrain tissue was determined according to ELISA method.

At the result, there showed no difference in the change of the amount ofA 42 and the amount of A 40 was slightly reduced through A 40 ELISAtest, which showed no significance statistically (See FIG. 13).

(c). Brain Sections Staining Using Low Temperature MaintainingApparatus.

Before staining, the left hemisphere of delivered brain was fixed in 10%formalin solution for overnight and transferred to 20% sucrose solutionfor 2 days to remove remaining water of the tissue. Using bylow-temperature maintaining apparatus, the tissue was cut to a thicknessof 40 μm with coronal and stored in store solution.

(d). Congo Red Staining Method.

The six tissue sections per mouse were placed on the slide glass andthen stained with 0.2% alkali Congo-Red solution. Thereafter, thestained tissues were dehydrated with 100% ethanol and treated withxylene to remove the dehydrating agent. Then the tissues were coveredwith cover glass by using balsam in order not to forming air bubble. Theexistence of a plaque in the tissues was observed through opticalmicroscope connecting with digital camera and the calculated number,size, and area of the plaque in the brain tissue were shown in FIG. 14.

As shown in the FIG. 14, the numbers, size, and area of plaque intransgenic mice treated with the compound 18b were significantly reduced(See FIG. 14).

Ab burden percentages indicates the ratio calculated from comparing withthe area of plague with the total area and the result was shown in FIG.15.

(e). ChAT Antibody Staining

Four tissue sections per mouse were added to PBST to flocculate and thenanti-ChAT was added thereto with a ratio of 1:100. The solution wasreacted together for overnight at 4° C. and the tissues were washed withPBST. Secondary antibody (HRP conjugated a-goat IgG antibody) was addedthereto and mixed together with the mixed ratio of 1:1000 at roomtemperature one hour before the reaction.

After washing again with PBST, the tissues were stained to brown colorwith DAB kit as a staining agent. The stained tissues were photographedusing by optical microscope connecting with distal camera and then thenumber of the ChAT positive neuron in the tissues was determined.

As shown in FIG. 15, it has been confirmed that the number of neuron intransgenic mice treated with the compound 18b was slightly increased(See FIG. 15).

Hereinafter, the formulating methods and kinds of excipients will bedescribed, but the present invention is not limited to them. Therepresentative preparation examples were described as follows.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications as would be obvious to one skilled in the art areintended to be included within the scope of the following claims.

Hereinafter, the formulating methods and kinds of excipients will bedescribed, but the present invention is not limited to them. Therepresentative preparation examples were described as follows.

Preparation of powder Compound (18b) 20 mg Lactose 100 mg  Talc 10 mg

Powder preparation was prepared by mixing above components and fillingsealed package.

Preparation of tablet Compound (11b)  10 mg Corn Starch 100 mg Lactose100 mg Magnesium Stearate  2 mg

Tablet preparation was prepared by mixing above components andentabletting.

Preparation of capsule Compound (18b)  10 mg Corn starch 100 mg Lactose100 mg Magnesium Stearate  2 mg

Tablet preparation was prepared by mixing above components and fillinggelatin capsule by conventional gelatin preparation method.

Preparation of injection Compound (11b) 10 mg Distilled water forinjection optimum amount PH controller optimum amount

Injection preparation was prepared by dissolving active component,controlling pH to about 7.5 and then filling all the components in 2ample and sterilizing by conventional injection preparation method.

Preparation of liquid Compound (18b)  20 mg Sugar 5~10 g Citric acid 0.05~0.3% Caramel 0.005~0.02% Vitamin C  0.1~1% Distilled water  79~94% CO₂ gas  0.5~0.82%

Liquid preparation was prepared by dissolving active component, fillingall the components and sterilizing by conventional liquid preparationmethod.

Preparation of health care food Compound (11b) 1000 mg Vitamin mixtureoptimum amount Vitamin A acetate 70 mg Vitamin E 1.0 mg Vitamin B₁ 0.13mg Vitamin B₂ 0.15 mg Vitamin B6 0.5 mg Vitamin B12 0.2 mg Vitamin C 10mg Biotin 10 mg Amide nicotinic acid 1.7 mg Folic acid 50 mg Calciumpantothenic acid 0.5 mg Mineral mixture optimum amount Ferrous sulfate1.75 mg Zinc oxide 0.82 mg Magnesium carbonate 25.3 mg Monopotassiumphosphate 15 mg Dicalcium phosphate 55 mg Potassium citrate 90 mgCalcium carbonate 100 mg Magnesium chloride 24.8 mg

The above-mentioned vitamin and mineral mixture may be varied in manyways. Such variations are not to be regarded as a departure from thespirit and scope of the present invention.

Preparation of health beverage Compound (18b) 1000 mg Citric acid 1000mg Oligosaccharide 100 g Apricot concentration 2 g Taurine 1 g Distilledwater 900 ml

Health beverage preparation was prepared by dissolving active component,mixing, stirred at 85□ for 1 hour, filtered and then filling all thecomponents in 1000 ml ample and sterilizing by conventional healthbeverage preparation method.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications as would be obvious to one skilled in the art areintended to be included within the scope of the following claims.

INDUSTRIAL APPLICABILITY

As described in the present invention, the novel benzofuran derivativesof the present invention showed potent inhibiting activity ofbeta-amyloid aggregation and cell cytotoxicity resulting in stimulatingthe proliferation of neuronal cells as well as recovering activity ofmemory learning injury caused by neuronal cell injury using transformedanimal model with beta-amyloid precursor gene, therefore the compoundscan be useful in treating or preventing cognitive function disorder.

The invention claimed is:
 1. A compound represented by general formula(I), or a pharmaceutically acceptable salt thereof:

wherein R₁ is a hydrogen atom, C₁-C₆ alkyl group, C₂-C₆ alkyl ketonegroup or —(CH₂)_(n)-Q, of which Q is an ether group or amine groupsubstituted with C₁-C₆ lower alkyl group; R₂ is a hydrogen atom, or anether group or thio group substituted with C₁-C₆ alkyl group; R₃ is

wherein P₁, P₂ is independently, at least one selected from the groupconsisting of a hydrogen atom, C₁-C₆ alkyl group, phenyl group, benzylgroup and 2-methyl-3-acetamide group, n is an integer of 0-9.
 2. Thecompound of claim 1, wherein R₁ is a methyl group, ethyl group,methylketone group or ethyl ketone group; Q is a methoxy group, anethoxy group, dimethylamino group or diethylamino group; R₂ is ahydrogen atom or methylthio group; R₃ is a group of general formula (Ic)wherein P₁, P₂ is independently a methyl group, an ethyl group, adimethyl group, a diethyl group or 2-methyl-3-acetamide group.
 3. Thecompound of claim 1, wherein said compound is selected from the groupconsisting of: N,N-diethyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,N,N-dimethyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,N-methyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,N,N-diethyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,N,N-dimethyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,N-methyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,(R)-2-(2-(2-(4-hydroxy-3-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide-4-methylpentanamide,N-phenyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,N-benzyl3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-propionamide,(R)-3-(2-[2-(4-hydroxy-3-methoxyphenyl)-3-(methylsulfanyl)-1-benzofuran-5-yl]-acetylamino-4-methylpentanamide,N-phenyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,N-benzyl2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]-acetamide,2-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]acetamide,3-[2-(4′-hydroxy-3′-methoxyphenyl)-3-(methylthio)-benzofuran-5-yl]propionamide,3-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dipropylpropanamide,3-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dipropylpropanamide,2-(2-(4-Hydroxy-3-methoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N,N-dimethylacetamide,2-(2-(3,4-Dimethoxyphenyl)-3-(methylthio)benzofuran-5-yl)-N-propylacetamide,N,N-Diethyl-3-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)propanamide,N,N-Diethyl-2-(2-(4-hydroxy-3-methoxyphenyl)benzofuran-5-yl)acetamide,2-(2-(4-Hydroxy-3-methoxyphenyl)benzofuran-5-yl)-N,N-dipropylacetamide,N,N-Diethyl-2-(2-(3,4-dimethoxyphenyl)benzofuran-5-yl)acetamide, and2-(2-(3,4-Dimethoxyphenyl)benzofuran-5-yl)-N,N-dimethylacetamide.
 4. Apharmaceutical composition comprising the compound represented bygeneral formula (I) as set forth in claim 1 or the pharmaceuticallyacceptable salt thereof, together with pharmaceutically acceptablecarriers or diluents.
 5. A method of treatment comprising administeringthe compound represented by general formula (I) as set forth in claim 1or the pharmacologically acceptable carrier thereof; to a human ormammal in need of treatment of a cognitive function disorder selectedfrom the group consisting of Alzheimer type dementia, cerebrovasculartype dementia, Creutzfeldt-jakob's disease, and Parkinson's disease. 6.A health care food comprising the compound represented by generalformula (I) as set forth in claim 1, or the pharmacologically acceptablesalt thereof, together with a sitologically acceptable additive for thealleviation of cognitive function disorder.
 7. The health care food ofclaim 6, the health care food is a form of powder, granule, tablet,capsule or beverage.
 8. A method of inhibiting accumulated beta-amyloidin a mammal comprising administering to said mammal the compoundrepresented by general formula (I) as set forth in claim 1 or thepharmacologically acceptable salt thereof, together with apharmaceutically acceptable carrier thereof.